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WO2008133884A2 - Methods and compositions for the treatment of neurodegenerative disorders - Google Patents

Methods and compositions for the treatment of neurodegenerative disorders Download PDF

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Publication number
WO2008133884A2
WO2008133884A2 PCT/US2008/005194 US2008005194W WO2008133884A2 WO 2008133884 A2 WO2008133884 A2 WO 2008133884A2 US 2008005194 W US2008005194 W US 2008005194W WO 2008133884 A2 WO2008133884 A2 WO 2008133884A2
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agent
agents
group
composition
tables
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PCT/US2008/005194
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French (fr)
Inventor
Xiaowei Jin
Jane Staunton
Douglas Macdonald
Hualing Dong
Lydia Kifle
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Combinatorx, Incorporated
Chdi, Inc.
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Publication of WO2008133884A2 publication Critical patent/WO2008133884A2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • this invention relates to the treatment, prevention, and amelioration of neurodegenerative disorders, e.g., Huntington's disease, and symptoms thereof.
  • Neurodegenerative disorders affect millions of individuals.
  • One class of these disorders, the polyglutamine expansion disorders is characterized by the presence of an expanded CAG repeat region within the coding sequence of a gene. While the threshold length of the CAG expansion is variable in these disorders, longer repeat length generally results in an earlier onset of the disease.
  • the threshold CAG repeat length for the onset of the disease is generally regarded as greater than 38 CAGs, resulting in a polyglutamine domain proximal to the N-terminus of the Huntingtin protein.
  • Huntington's disease one of at least nine known inherited polyglutamine expansion disorders, affects men and women with equal frequency, about 5-10 per 100,000. It can be characterized by five hallmark features: heritability; chorea; behavioral or psychiatric disturbances; cognitive impairment (dementia); and late-onset, with death occurring 15-20 years post- onset of motor dysfunctions. In most patients, the onset of the disease occurs in the third to fifth decade of life.
  • HD is an autosomal dominant disorder with a gene mutation on chromosome 4. This gene encodes a large protein, huntingtin (Htt), with multiple important functions. HD is caused by an expansion of the CAG repeat in the huntingtin (htt) gene, resulting in an expanded polyglutamine (poly Q) region near the N-terminus of Htt.
  • htt huntingtin
  • poly Q polyglutamine
  • HD pathologic mechanisms underlying HD are not yet completely understood.
  • Leading hypotheses include excitotoxicity, mitochondrial dysfunction, deficiencies in ubiquitin-mediated proteolysis, protease-dependent accumulation of poly-glutamine protein fragments, formation of cytosolic and nuclear inclusions, changes in gene expression, and neuronal cell degeneration and death.
  • apoptosis plays an important role.
  • There are no current HD therapies although some patients treat their symptoms with conventional neuroleptics to decrease chorea, and psychotropic medications to address depression, obsessive compulsive symptoms, or psychosis.
  • compositions, methods, and kits for treating, preventing, and ameliorating neurodegenerative disorders may be useful for treating patients having or at risk of having a polyglutamine expansion disorder, such as HD.
  • the compositions, methods, and kits described herein also may be useful for treating symptoms or complications associated with neurodegenerative disorders, e.g., chorea, depression, obsessive-compulsive behavior, psychosis, dystonia (e.g., jaw clenching), and behavioral disturbances.
  • compositions that includes one or more first agents selected independently from the agents of Tables Ia and Ib, and one or more second, different agents selected independently from the classes and agents of Tables Ia, Ib, and 2.
  • the agent or agents of Tables Ia and Ib can be, e.g., tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, selective serotonin reuptake inhibitors ("SSRIs”), anticholinergics, IKK- ⁇ inhibitors, or estrogen modulators.
  • the first and second agents are selected from a single row of Tables 3a and 3b.
  • the first agent and second agent are present in amounts that, when administered to a patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder, e.g., a disorder selected from the group consisting of a polyglutamine expansion disorder (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), another trinucleotide repeat expansion disorder (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Bat
  • compositions consisting of active ingredients and pharmaceutically acceptable carriers, wherein the active ingredients consist of a first agent selected independently from the agents of Tables Ia and Ib, and a second, different agent selected independently from the classes and agents of Tables Ia, Ib, and 2.
  • the first and second agents are selected from a single row of Tables 3a and 3b.
  • the first and second agents are selected from a single row of Tables 3a and 3b.
  • the first and second agents may be administered simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days of each other.
  • the agent or agents administered to the patient may reduce the rate of neuronal death in the patient (e.g., a human) relative to the rate of neuronal death in a control.
  • the methods may include an additional therapeutic regimen.
  • the additional therapeutic regimen may include administering to the patient an additional therapeutic agent, such that the agent or agents selected from Tables Ia and Ib and the additional therapeutic agent are present in amounts that, when administered to the patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder.
  • the additional therapeutic agent may be, e.g., selected from the classes and agents of Table 2.
  • the agent or agents from Tables Ia or Ib and the additional therapeutic agent may be administered simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days of each other, via any route of administration.
  • kits that includes an agent selected from the agents of Tables Ia and Ib and instructions for administering the agent to a patient having or at risk of having a neurodegenerative disorder.
  • the kit includes two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib that may, but need not be, admixed in the same composition.
  • This kit may also include instructions for administering the additional agent or agents, or the admixed composition, to the patient.
  • kits that includes one, two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib and one or more agents selected independently from the classes and agents of Table 2.
  • the agents may, but need not, be admixed in the same composition.
  • the kit also includes instructions for administering these agents to a patient having or at risk of having a neurodegenerative disorder.
  • kits that includes either one, two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib, or one or more agents selected independently from the classes and agents of Table 2.
  • the kit also includes instructions for administering these agents together to a patient having or at risk of having a neurodegenerative disorder.
  • two agents may be selected from a single row of Tables 3a and 3b.
  • Also provided is a method of identifying a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder including the steps of: (a) providing cells that include a gene encoding a polyglutamine repeat polypeptide, such that the polypeptide includes an expanded polyglutamine repeat region relative to a wild-type polyglutamine repeat polypeptide; (b) inducing expression of the gene; (c) contacting the cells with an agent selected from the agents of Tables Ia and Ib and a candidate compound; and (d) determining whether the combination of the agent and the candidate compound reduces perinuclear staining by a polyQ antibody, e.g., 1F8, relative to cells contacted with the agent but not contacted with the candidate compound, wherein a reduction in perinuclear staining (as determined, e.g., by immunocytochemistry (ICC) analysis) identifies the combination as a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder.
  • the polyglutamine repeat polypeptide that includes the expanded polyglutamine repeat region may include, e.g., full-length Htt Ql 11, or another variant of a polypeptide associated with a polyglutamine expansion disorder.
  • the method may use, e.g., mammalian cells, e.g., mouse striatal cells, e.g., STHdhQl 11 cells derived from knock- in mice.
  • an amount sufficient is meant the amount of a compound, alone or in combination with another therapeutic regimen, required to treat, prevent, or ameliorate a neurodegenerative disorder, such as HD, in a clinically relevant manner.
  • a sufficient amount of an active compound used for therapeutic treatment of neurodegenerative disorders varies depending upon the manner of administration, age, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of compound in the combination that is safe and efficacious in the treatment of a patient having a neurodegenerative disorder, such as HD, over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug
  • Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof.
  • Compounds include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein.
  • Compounds may also be isotopically labeled compounds.
  • Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl).
  • Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non- isotopically-labeled reagent.
  • expanded polyglutamine repeat region is meant a region of a polyglutamine repeat polypeptide in which the number of glutamine residues is greater than the number of glutamine residues in a corresponding wild-type polypeptide.
  • An exemplary polypeptide containing an expanded polyglutamine repeat region is, e.g., full-length HttQl 11, which contains a region of 111 glutamine residues.
  • An expanded polyglutamine repeat region contains greater than, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or even 100 glutamine residues.
  • an expanded polyglutamine repeat region contains greater than, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40,
  • a high dosage is meant at least 5% more (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • a high dosage of an agent that prevents or slows the rate of neural deterioration or death associated with a neurodegenerative disorder and that is formulated for intravenous administration may differ from a high dosage of the same agent formulated for oral administration.
  • a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
  • neurodegenerative disorder any disease or disorder caused by or associated with the deterioration of cells or tissues of the nervous system.
  • exemplary neurodegenerative disorders are polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-S
  • patient any animal, e.g., a mammal (e.g., a human).
  • Other animals that can be treated using the methods, compositions, and kits described herein include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • a patient who is being treated for a neurodegenerative disorder is one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means, such as those described herein. A patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis.
  • a neurodegenerative disorder e.g., HD
  • a patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis.
  • patients may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors, such as age, family history of neurodegenerative disorders, and psychological or psychiatric profile.
  • polyglutamine repeat polypeptide is meant any polypeptide containing at least five consecutive glutamine residues.
  • Exemplary polyglutamine repeat polypeptides are those associated with polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)).
  • polyglutamine expansion disorders e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)
  • Htt which is associated with HD, is a polyglutamine repeat polypeptide.
  • polypeptide and “peptide” are used interchangeably and refer to any chain of more than two natural or unnatural amino acids, regardless of post-translational modification (e.g., glycosylation or phosphorylation), constituting all or part of a naturally-occurring or non-naturally occurring polypeptide or peptide, as is described herein.
  • a natural amino acid is a natural ⁇ -amino acid having the L-conf ⁇ guration, such as those normally occurring in natural proteins.
  • Unnatural amino acid refers to an amino acid, which normally does not occur in proteins, e.g., an epimer of a natural ⁇ -amino acid having the L configuration, that is to say an amino acid having the unnatural D- configuration; or a (D,L)-isomeric mixture thereof; or a homologue of such an amino acid, for example, a ⁇ -amino acid, an ⁇ , ⁇ -disubstituted amino acid, or an ⁇ -amino acid wherein the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms, such as an ⁇ - amino alkanoic acid with 5 up to and including 10 carbon atoms in a linear chain, an unsubstituted or substituted aromatic ( ⁇ -aryl or ⁇ -aryl lower alkyl), for example, a substituted phenylalanine or phenylglycine.
  • an amino acid side chain has been shortened by one or two methylene groups or lengthened
  • systemic administration is meant any nondermal route of administration, and specifically excludes topical and transdermal routes of administration.
  • treating, preventing, or ameliorating a neurodegenerative disorder is meant ameliorating such a condition before or after its onset. As compared with an equivalent untreated control, such amelioration or degree of prevention is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 6 carbon atoms or Ci-C 6 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range.
  • an alkyl group from 1 to 6 carbon atoms includes each Of C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 .
  • a CpCi 2 heteroalkyl for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.
  • alkyl and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl.
  • Cyclic groups can be monocyclic or polycyclic and, in some embodiments, have from 3 to 6 ring carbon atoms, inclusive.
  • Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • C 1 -C 6 alkyl is meant a branched or unbranched hydrocarbon group having from 1 to 6 carbon atoms.
  • a C 1 -C 6 alkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 1 -C 6 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.
  • C 2 -C 6 alkenyl is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms.
  • a C 2 -C 6 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members.
  • the C 2 -C 6 alkenyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2 -C 6 alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-l-ethenyl, 1-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1-propenyl, and 2-methyl-2-propenyl.
  • C 2 -C 6 alkynyl is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms.
  • a C 2 -C 6 alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the C 2 - C 6 alkynyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • C 2 -C 6 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, and 3-butynyl.
  • C 2 -C 6 heterocyclyl is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom.
  • a nitrogen atom in the heterocycle may optionally be quaternized.
  • Heterocycles include, without limitation, lH-indazole, 2-pyrrolidonyl, 2H,6H-l,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH- carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-
  • 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, IH- indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl.
  • 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
  • C 6 -Ci 2 aryl is meant an aromatic group having a ring system comprised of carbon atoms with conjugated ⁇ electrons (e.g., phenyl).
  • the aryl group has from 6 to 12 carbon atoms.
  • Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members.
  • the aryl group may be substituted or unsubstituted.
  • substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
  • C 7 -Ci 4 alkaryl is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
  • C 3 -Ci 0 alkheterocyclyl is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2- tetrahydrofuranylmethyl).
  • Ci-C 7 heteroalkyl is meant a branched or unbranched alkyl, alkenyl, or alkyny 1 group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P.
  • Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides.
  • a heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members.
  • the heteroalkyl group may be substituted or unsubstituted.
  • substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
  • Ci-C 7 heteroalkyls include, without limitation, methoxymethyl and ethoxy ethyl.
  • halogen is meant bromine, chlorine, iodine, or fluorine.
  • fluoroalkyl is meant an alkyl group that is substituted with a fluorine atom.
  • perfluoroalkyl is meant an alkyl group consisting of only carbon and fluorine atoms.
  • carboxyalkyl is meant a chemical moiety with the formula
  • R is selected from C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 heterocyclyl, C 6 -C 12 aryl, C 7 -C 14 alkaryl, C 3 -Cj 0 alkheterocyclyl, and C 1 -C 7 heteroalkyl.
  • hydroxyalkyl is meant a chemical moiety with the formula -(R)- OH, wherein R is selected from C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 - C 6 heterocyclyl, C 6 -Ci 2 aryl, C 7 -C 14 alkaryl, C 3 -C 10 alkheterocyclyl, and C 1 -C 7 heteroalkyl.
  • alkoxy is meant a chemical substituent of the formula -OR, wherein R is selected from CpC 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 heterocyclyl, C 6 -Ci 2 aryl, C 7 -C 14 alkaryl, C 3 -C 10 alkheterocyclyl, and Ci-C 7 heteroalkyl.
  • aryloxy is meant a chemical substituent of the formula -OR, wherein R is a C 6 -C 12 aryl group.
  • alkylthio is meant a chemical substituent of the formula -SR, wherein R is selected from Ci -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 6 heterocyclyl, C 6 -Ci 2 aryl, C 7 -Ci 4 alkaryl, C 3 -C] 0 alkheterocyclyl, and C 1 -C 7 heteroalkyl.
  • arylthio is meant a chemical substituent of the formula -SR, wherein R is a C 6 -Ci 2 aryl group.
  • quaternary amino is meant a chemical substituent of the formula
  • R, R', R", and R'" are each independently an alkyl, alkenyl, alkynyl, or aryl group.
  • R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety.
  • the nitrogen atom, N is covalently attached to four carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom.
  • compositions, methods, and kits described herein may be useful for treating patients having or at risk of having a polyglutamine expansion disorder, e.g., HD. Accordingly, a patient that has been diagnosed with or is at risk of having a neurodegenerative disorder is administered one, two, three, four, or more agents selected independently from any of the agents of Tables Ia and Ib. Optionally, analogs of these agents may be employed. In the case of a polyglutamine expansion disorder, for example, such administration may prevent or slow the rate of neural deterioration or death.
  • the ability of the agent to prevent or slow the rate of neural deterioration or death may be attributed, for example, to its ability to inhibit the disease-causing activity of a mutant polyglutamine protein, e.g., Htt.
  • the patient may also receive other therapeutic regimens.
  • the patient being treated is administered two agents selected independently from any of the agents of Tables Ia and Ib within 28 days of each other in amounts that together are sufficient to treat, prevent, or ameliorate the neurodegenerative disorder.
  • the two agents are desirably administered within 14 days of each other, more desirably within seven days of each other, and even more desirably within twenty- four hours of each other, or even simultaneously. If desired, either one of the two agents may be administered in low dosage.
  • the methods and compositions described herein may be useful for treating any patient that has been diagnosed with or is at risk of having a neurodegenerative disorder, such as HD.
  • a patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis.
  • a patient may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • Diagnosis of neurodegenerative disorders, e.g., HD may be performed using any standard method known in the art, such as those described herein. Methods for diagnosing such disorders are described, for example, in U.S. Patent Nos. 6,355,481 and 6,210,970.
  • HD may be diagnosed and monitored, for example, by performing genetic tests (e.g., by sequencing the htt gene and testing for the presence of an expanded CAG repeat region); neurological examination, e.g., testing body movement, reflexes, eye movement, hearing, or balance, and/or performing brain imaging; evaluating family history of disease; or conducting a psychological or psychiatric interview.
  • Symptoms or altered behavior that can lead to a diagnosis of HD include, e.g., aggression, altered sexuality, anxiety, apathy, delusions, denial, depression, disinhibition, frustration, hallucinations, irritability, mania, repetition, and lack of awareness.
  • a patient may be diagnosed as having or being at risk of having HD if a genetic test is performed and the number of CAG repeats in the htt gene is greater than a threshold number, e.g., 38. A larger number of repeats is generally associated with an earlier onset of disease. Similar diagnostic methods may be used, e.g., for any of the polyglutamine expansion disorders. In addition, genetic, neurological, and/or behavioral testing may be used to diagnose other neurodegenerative disorders. Therapeutic Agents
  • An effective amount of one, two, three, four, or more agents selected independently from any of the agents of Tables Ia and Ib may be administered to a patient having, or being at risk of having, a neurodegenerative disorder, thereby treating, preventing, or ameliorating such a disorder.
  • an agent described herein may inhibit the disease-causing activity of a mutant Htt protein, e.g., by preventing or reducing Htt aggregation.
  • compositions, methods, and kits described herein include tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, SSRIs, anticholinergics, EKK- ⁇ inhibitors, and estrogen modulators, as described in more detail below.
  • Tricyclic antidepressants generally work by inhibiting the re- uptake of neurotransmitters, such as norepinephrine, dopamine, or serotonin, by nerve cells. TCAs may be used to treat neurodegenerative disorders.
  • TCAs that may be suitable for use in the compositions, kits, and methods described herein include, e.g., amoxapine, amitriptyline, BTCP hydrochloride, clomipramine (e.g., clomipramine hydrochloride), desipramine, dothiepin, doxepin, duloxetine, fluoxetine hydrochloride, fluvoxamine maleate, 7- hydroxyamoxapine, 8-hydroxyamoxapine, 8-hydroxyloxapine, imipramine, lofepramine, loxapine (e.g., loxapine succinate, loxapine hydrochloride), maprotiline hydrochloride, norfluoxetine, nortriptyline (e.g., nortriptyline hydrochloride), paroxetine hydrochloride, protriptyline, sertraline hydrochloride, and trimipramine.
  • clomipramine e.g., clomi
  • Nortriptyline has the structure:
  • Exemplary analogs of nortriptyline are amitriptylin, amoxapine, butriptyline, clomipramine, dothiepin, doxepin, desipramine, 8- hydroxyamoxapine, 7-hydroxyamoxapine, 8-hydroxyloxapine, imipramine, iprindole, lofepramine, loxapine, loxapine succinate, loxapine hydrochloride, maprotiline, mianserin, octriptyline, opipramol, oxaprotiline, protriptyline, trimipramine, and pharmaceutically acceptable salts thereof (described, e.g., in U.S.
  • Patent Nos. 4,933,438 and 4,931,435) which are tricyclic antidepressants or act by blocking neuroepinephrine transport. Analogs of nortriptyline are also described by Formula PP in U.S. Application Publication No. 2005- 0080265.
  • Ionophores disrupt transmembrane ion concentration gradients, required for the proper functioning and survival of cells, and thus have antibiotic properties.
  • Ionophore antibiotics may be used to treat neurodegenerative disorders.
  • Ionophore antibiotics that may be suitable for use in the compositions, kits, and methods described herein include, e.g., alborixin, antibiotic A204, antibiotic X206, antibiotic A32887, antibiotic X-14766A, beauvericin, calcimycine (also referred to as A23187), calixarene, CCCP, chlorogenic acid, Compound 47,224, Compound 51,532, crown ether, dianemycin, dinactin, 2,4-dinitrophenol, NjN-dioctadecylmethylamine (also referred to as Proton ionophore III), etheromycin, FCCP, gramicidin A, grisorixin, ionomycin, isolasalocid A, K41, lasaloci
  • Analogs of Maduramicin include the other polyether antiobiotics named above.
  • Cannabinoid Agonists include a group of substances that are structurally related to THC or that bind to cannabinoid receptors (e.g., diterpene C21 compounds present in Cannabis sativa L). Cannabinoid agonists may be used to treat neurodegenerative disorders.
  • Cannabinoid agonists that may be suitable for use in the compositions, kits, and methods described herein include, e.g., ajulemic acid (IP-751), CP-55940, HU210, SR141716, SR144528, WIN 55,212-2, JWH-133, nabilone, levonantradol, marinol, sativex, tetrahydrocannabinol (THC), and analogs thereof.
  • WIN 55,212-2 has the following structure:
  • Analogs of WIN 55,212-2 include ligands and modulators of the CBl receptor and include: SR 141716A; Formulas (II) and (III) in U.S. Patent No. 6,825,209; Formulas (I) and (II) in U.S. Patent No. 5,596,106; and Formula (I) in U.S. Patent No. 6,509,367.
  • Channel Blockers are compounds, ranging from ions to complex organic molecules, that block the flow of ions through an ion channel. Channel blockers may be used to treat neurodegenerative disorders. Channel blockers that may be suitable for use in the compositions, kits, and methods described herein include, e.g., calcium channel blockers and sodium channel blockers.
  • Calcium channel blockers include, e.g., dihydropyridines (e.g., amlodipine (e.g., amlodipine besylate); felodipine; lacidipine; lercanidipine; nicardipine; nifedipine; nimodipine; nisoldipine; and nitrendipine); phenylalkylamines (e.g., gallopamil and verapamil); benzodiazepines (e.g., diltiazem); and other agents, e.g., BAPTA-AM; bepridil; magnesium; and menthol; and paramethadione.
  • dihydropyridines e.g., amlodipine (e.g., amlodipine besylate); felodipine; lacidipine; lercanidipine; nicardipine; nifedipine; nimodipine
  • Sodium channel blockers include, e.g., dibucaine (e.g., dibucaine hydrochloride); disopryamide; dyclonine (e.g., dyclonine hydrochloride); flecainide; lidocaine; mexiletine; moricizine; phenytoin; procainamide; propafenone; quinidine (e.g., quinidine gluconate); and tocainide.
  • Additional channel blockers that may be useful include, e.g., levetiracetam.
  • Bepridil has the following structure:
  • Antihistamines are compounds that block the action of histamine.
  • Antihistamines may be used to treat neurodegenerative disorders.
  • Classes of antihistamines include:
  • Ethanolamines e.g., bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxylamine
  • Ethylenediamines e.g., pheniramine, pyrilamine, tripelennamine, and triprolidine
  • Phenothiazines e.g., diethazine, ethopropazine, methdilazine (e.g., methdilazine hydrochloride), promethazine, thiethylperazine, and trimeprazine
  • Alkylamines e.g., acrivastine, brompheniramine, chlorpheniramine, desbrompheniramine, dexchlorpheniramine, pyrrobutamine, and triprolidine
  • Piperazines e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine
  • Piperidines e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine
  • Piperazines e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine
  • Piperidines e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine
  • Atypical antihistamines e.g., azelastine, levocabastine, methapyrilene, and phenyltoxamine.
  • nonsedating and sedating antihistamines may be employed.
  • Exemplary antihistamines that may be used in the methods, compositions, and kits described herein are non-sedating antihistamines such as loratadine and desloratadine. Sedating antihistamines may also be used in the methods, compositions, and kits described herein.
  • Exemplary sedating antihistamines of the methods, compositions, and kits described herein are azatadine, bromodiphenhydramine; chlorpheniramine; clemizole; cyproheptadine (e.g., cyproheptadine hydrochloride); dimenhydrinate; diphenhydramine; doxylamine; meclizine; promethazine (e.g., promethazine hydrochloride); pyrilamine; thiethylperazine; and tripelennamine.
  • azatadine bromodiphenhydramine
  • chlorpheniramine clemizole
  • cyproheptadine e.g., cyproheptadine hydrochloride
  • dimenhydrinate diphenhydramine
  • doxylamine meclizine
  • promethazine e.g., promethazine hydrochloride
  • pyrilamine thiethylperazine
  • antihistamines that may be suitable for use in the methods, compositions, and kits described herein are acrivastine; ahistan; antazoline (e.g., antazoline phosphate); astemizole; azelastine (e.g., azelsatine hydrochloride); bamipine; bepotastine; bietanautine; brompheniramine (e.g., brompheniramine maleate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; chloropyramine; chlorothen; chlorphenoxamine; cinnarizine; clemastine (e.g., clemastine fumarate); clobenzepam; clobenztropine; clocinizine; cyclizine (e.g., cyclizine hydrochloride; cyclizin
  • Antihistamine analogs include, without limitation, 10-piperazinylpropylphenothiazine; 4-(3- (2-chlorophenothiazin- 10-yl)propyl)- 1 -piperazineethanol dihydrochloride; 1 - ( 10-(3 -(4-methy 1- 1 -piperaziny l)propy I)- 1 OH-phenothiazin-2-y 1)-(9CI) 1 - propanone; 3-methoxycyproheptadine; 4-(3-(2-Chloro-10H-phenothiazin-10- yl)propyl)piperazine-l-ethanol hydrochloride; 10,1 l-dihydro-5-(3-(4- ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H- dibenzo(a,d)cycloheptene; aceprometazine;
  • DF-1111301 ; EL-301; elbanizine; F-7946T; F-9505; HE-90481; HE-90512; hivenyl; HSR-609; icotidine; KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674; levocetirizine; levoprotiline; metoclopramide; NIP-531; noberastine; oxatomide; PR-881-884A; quisultazine; rocastine; selenotifen;
  • UCB-35440 VUF-K-8707; Wy-49051; and ZCR-2060.
  • Clemastine has the following structure:
  • Exemplary clemastine analogs include: N-methy 1-2- [2 '-(p- chlorobenzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2' -benzyhy dry loxy)- ethyl]-piperidine; N-methyl-2-[2'-(p-bromo-benzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2 ' -(p-fluoro-benzhy dry loxy )-ethy 1] -piperidine; N-methy 1-2- [2 ' - (p-methyl-benzhydryloxy)-ethyl]-piperidine; N-methyl-2-[2'-(p- methoxyzbenzhydryloxy) ethyl]-piperidine; N-methy 1-2- [2'- ( -methyl- benzhydryloxy)-ethyl]-
  • Cyproheptadine has the following structure:
  • R 1 , R 2 , R 3 , R 4 , K 5 , R 6 , R 7 , and Rg are each selected from H, C 1-6 alkyl, perhalogenated C 1-6 alkyl, OH, OCi -6 alkyl, OCF 3 , SH, SC 1 .
  • Y is CH 2 , O, NH, S(O) 0-2 , (CH 2 ) 3 , (CH) 2 , CH 2 O, CH 2 NH, CHN, or CH 2 S;
  • A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive;
  • R 9 is H or Ci -6 alkyl;
  • B 1 and B 2 are selected from H, perhalogenated C 1-6 alkyl, Ci -6 alkyl, or B 1 and B 2 , B 1 and R 9 , or B 2 and R 9 join together to form an optionally substituted ring.
  • Suitable SSRIs may include amoxapine; BTCP (e.g., BTCP hydrochloride); cericlamine (e.g., cericlamine hydrochloride); citalopram (e.g., citalopram hydrobromide); clovoxamine; cyanodothiepin; dapoxetine; dothiepin; duloxetine; escitalopram (escitalopram oxalate); femoxetine (e.g., femoxetine hydrochloride); fenfluramine (e.g., fenfluramine hydrochloride); fluoxetine (e.g., fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride
  • Cericlamine Cericlamine has the following structure:
  • Structural analogs of cericlamine are those having the formula:
  • R 1 is a C 1 -C 6 alkyl and R 2 is H or Q-C 6 alkyl
  • R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenylalkyl or cycloalkylalkyl with 3 to 6 cyclic carbon atoms, alkanoyl, phenylalkanoyl or cycloalkylcarbonyl having 3 to 6 cyclic carbon atoms, or R 2 and R 3 form, together with the nitrogen atom to which they are linked, a heterocycle saturated with 5 to 7 chain links which can have, as the second heteroatom not directly connected to the nitrogen atom, an oxygen, a sulphur or a nitrogen, the latter nitrogen heteroatom possibly carrying a C 2 -C 6 alkyl.
  • cericlamine structural analogs are 2-methyl-2-amino-3-(3,4- dichlorophenyl)-propanol, 2-pentyl-2-amino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2-methylamino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2- dimethylamino-3-(3,4-dichlorophenyl)-propanol, and pharmaceutically acceptable salts of any thereof. Citalopram
  • Citalopram has the following structure:
  • Structural analogs of citalopram are those having the formula:
  • each Of R 1 and R 2 is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, cyano and R-CO-, wherein R is C 1 -C 6 alkyl.
  • Exemplary citalopram structural analogs are l-(4'-fluorophenyl)-l-(3-dimethylaminopropyl)-5- bromophthalane; l-(4'-chlorophenyl)-l-(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-bromophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -(4'-bromophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -
  • Clovoxamine has the following structure:
  • Structural analogs of clovoxamine are those having the formula:
  • Hal is a chloro, bromo, or fluoro group and R is a cyano, methoxy, ethoxy, methoxy methyl, ethoxymethyl, methoxyethoxy, or cyanomethyl group.
  • Exemplary clovoxamine structural analogs are 4'-chloro-5- ethoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-5-(2- methoxyethoxy)valerophenone O-(2-aminoethyl)oxime; 4'-chloro-6- methoxycaprophenone O-(2-aminoethyl)oxime; 4'-chloro-6- ethoxycaprophenone O-(2-aminoethyl)oxime; 4'-bromo-5-(2- methoxyethoxy)valerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- methoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-6- cyanocaprophenone O-(2-aminoethyl)oxime; 4'-chloro-5-cyanovalerophenone O
  • Femoxetine has the following structure:
  • Structural analogs of femoxetine are those having the formula:
  • Ri represents a Ci-C 6 alkyl or C 2 -C 6 alkynyl group, or a phenyl group optionally substituted by C 1 -C 6 alkyl, CpC 6 alkylthio, CpC 6 alkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy, or tetrahydronaphthyl
  • R 2 represents a C 1 -C 6 alkyl or C 2 -C 6 alkynyl group
  • R 3 represents hydrogen, C 1 -C 6 alkyl, C]-C 6 alkoxy, trifluoroalkyl, hydroxy, bromo, chloro, fluoro, methylthio, or aralkyloxy.
  • Fluoxetine has the following structure:
  • Structural analogs of fluoxetine are those compounds having the formula:
  • each R 1 is independently hydrogen or methyl; R is naphthyl or
  • each of R 2 and R 3 is, independently, bromo, chloro, fluoro, trifluoromethyl, Q-C 6 alkyl, C 1 -C 3 alkoxy or C 3 -C 4 alkenyl; and each of n and m is, independently, 0, 1 or 2.
  • R is naphthyl, it can be either ⁇ -naphthyl or ⁇ -naphthyl.
  • Exemplary fluoxetine structural analogs are 3-(p-isopropoxyphenoxy)-3- phenylpropylamine methanesulfonate, N,N-dimethyl 3-(3',4'- dimethoxyphenoxy)-3 -phenylpropy lamine p-hy droxybenzoate, N,N-dimethy 1 3-( ⁇ -naphthoxy)-3-phenylpropylamine bromide, N,N-dimethyl 3-( ⁇ - naphthoxy)-3-phenyl-l-methylpropy lamine iodide, 3-(2'-methyl-4',5 l - dichlorophenoxy)-3 -phenylpropy lamine nitrate, 3-(p-t-butylphenoxy)-3- phenylpropylamine glutarate, N-methyl 3-(2'-chloro-p-tolyloxy)-3-phenyl-l- methylpropylamine lactate, 3-(2',4
  • Fluvoxamine has the following structure:
  • Structural analogs of fluvoxamine are described by Formula (I) in U.S. Patent No. 4,085,225. Structural analogs of fluvoxamine are also described by the formula:
  • R is cyano, cyanomethyl, methoxymethyl, or ethoxymethyl.
  • Indalpine has the following structure:
  • Structural analogs of indalpine are those having the formula:
  • R 1 is a hydrogen atom, a CpC 6 alkyl group, or an aralkyl group of which the alkyl has 1 or 2 carbon atoms
  • R 2 is hydrogen, Q-C 6 alkyl, CpC 6 alkoxy or CpC 6 alkylthio, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy, or amino, the latter optionally substituted by one or two Cj-C 6 alkyl groups, an acyl group or a C 1 -C 6 alkylsulfonyl group
  • A represents -CO or -CH 2 - group
  • n is 0, 1 or 2.
  • indalpine structural analogs are indolyl-3 (piperidyl-4 methyl) ketone; (methoxy-5-indolyl-3) (piperidyl-4 methyl) ketone; (chloro-5- indolyl-3) (piperidyl-4 methyl) ketone; (indolyl-3 )-l(piperidyl-4)-3 propanone, indolyl-3 piperidyl-4 ketone; (methyl- 1 indolyl-3) (piperidyl-4 methyl) ketone, (benzyl- 1 indolyl-3) (piperidyl-4 methyl) ketone; [(methoxy-5 indolyl-3)-2 ethyl]-piperidine, [(methyl- 1 indolyl-3)-2 ethyl] -4-piperi dine; [(indolyl-3 )-2 ethyl]-4 piperidine; (indolyl-3 methyl)
  • Indeloxezine has the following structure:
  • Structural analogs of indeloxazine are those having the formula:
  • R 1 and R 3 each represents hydrogen, C 1 -C ⁇ alkyl, or phenyl
  • R 2 represents hydrogen, C 1 -C 6 alkyl, C 4 -C 7 cycloalkyl, phenyl, or benzyl
  • one of the dotted lines means a single bond and the other means a double bond, or the tautomeric mixtures thereof.
  • Exemplary indeloxazine structural analogs are 2-(7-indenyloxymethyl)- 4-isopropylmo ⁇ holine; 4-butyl-2-(7-indenyloxymethyl)morpholine; 2-(7- indenyloxymethyl)-4-methylmorpholine; 4-ethyl-2-(7- indenyloxymethyl)mo ⁇ holine, 2-(7-indenyloxymethyl)-morpholine; 2-(7- indenyloxymethyl)-4-propylmo ⁇ holine; 4-cyclohexyl-2-(7- indenyloxymethyl)mo ⁇ holine; 4-benzyl-2-(7-indenyloxymethyl)-mo ⁇ holine; 2-(7-indenyloxymethyl)-4-phenylmo ⁇ holine; 2-(4- indenyloxymethyl)mo ⁇ holine; 2-(3-methyl-7-indenyloxymethyl)-mo ⁇ holine; 4-isopropyl-2-(3-
  • Milnacipram has the following structure:
  • each R independently, represents hydrogen, bromo, chloro, fluoro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, nitro or amino
  • each of Rj and R 2 independently, represents hydrogen, Q-C 6 alkyl, C 6 -Ci 2 ar yl or C 7 -C 14 alkylaryl, optionally substituted, for example, in para position, by bromo, chloro, or fluoro, or Rj and R 2 together form a heterocycle having 5 or 6 members with the adjacent nitrogen atoms
  • R 3 and R 4 represent hydrogen or a CpC 6 alkyl group or R 3 and R 4 form with the adjacent nitrogen atom a heterocycle having 5 or 6 members, optionally containing an additional heteroatom selected from nitrogen, sulphur, and oxygen.
  • Exemplary milnacipram structural analogs are 1 -phenyl 1- aminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- ethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- diethylaminocarbonyl 2-aminomethyl cyclopropane; 1 -phenyl 2- dimethylaminomethyl N-(4'-chlorophenyl)cyclopropane carboxamide; 1- phenyl 2-dimethylaminomethyl N-(4'-chlorobenzyl)cyclopropane carboxamide; 1 -phenyl 2-dimethylaminomethyl N-(2-phenylethyl)cyclopropane carboxamide; (3,4-dichloro-l -phenyl) 2-dimethylamino
  • Paroxetine Paroxetine has the following structure:
  • Structural analogs of paroxetine are those having the formula:
  • Rj represents hydrogen, optionally substituted Ci -6 alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 alkynyl
  • R 2 is optionally substituted Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2 -C 6 -heterocyclyl or C 6 -Ci 2 aryl
  • X is any halogen and may be in any of the available positions
  • Y is O or S.
  • Paroxetine analogs may be used as stereochemical mixtures or in stereochemically pure form.
  • An exemplary value for R 2 is optionally substituted 1,3-benzodioxole.
  • Sertraline has the following structure:
  • Structural analogs of sertraline are those having the formula: wherein, independently, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen or optionally substituted C 1 -G 6 alkyl; X and Y are each selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, C 1 -C 3 alkoxy, and cyano; and W is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and C 1 -C 3 alkoxy.
  • the sertraline analogs are in the cis-isomeric configuration.
  • cis-isomeric refers to the relative orientation of the NRiR 2 and phenyl moieties on the cyclohexene ring (i.e. they are both oriented on the same side of the ring). Because both the 1- and 4- carbons are asymmetrically substituted, each cis- compound has two optically active enantiomeric forms denoted (with reference to the 1 -carbon) as the cis-(lR) and cis-(l S) enantiomers.
  • Sertraline analogs are also described in U.S. Pat. No. 4,536,518.
  • Other related compounds include (S,S)-N-desmethylsertraline, rac-cis-N- desmethylsertraline, (lS,4S)-desmethyl sertraline, 1-des (methylamine)-l-oxo- 2-(R,S)-hydroxy sertraline, (lR,4R)-desmethyl sertraline, sertraline sulfonamide, sertraline (reverse) methanesulfonamide, 1R,4R sertraline enantiomer, N,N-dimethyl sertraline, nitro sertraline, sertraline aniline, sertraline iodide, sertraline sulfonamide NH 2 , sertraline sulfonamide ethanol, sertraline nitrile, sertraline-CME, dimethyl sertraline reverse sulfonamide, sertraline reverse sulfonamide (CH 2 linker
  • Zimeldine has the following structure:
  • Structural analogs of zimeldine are those compounds having the formula:
  • pyridine nucleus is bound in ortho-, meta- or para-position to the adjacent carbon atom and where R 1 is selected from the group consisting of H, chloro, fluoro, and bromo.
  • Exemplary zimeldine analogs are (e)- and (z)- 3-(4'-bromophenyl-3-(2"- pyridyl)-dimethylallylamine; 3-(4'-bromophenyl)-3-(3 "-pyridyl)- dimethylallylamine; 3-(4'-bromophenyl)-3-(4"-pyridyl)-dimethylallylamine; and pharmaceutically acceptable salts of any thereof.
  • Structural analogs of any of the above SSRIs are considered herein to be SSRI analogs and thus may be employed in any of the methods, compositions, and kits described herein.
  • Pharmacologically active metabolites of any of the foregoing SSRIs can also be used in the methods, compositions, and kits described herein.
  • Exemplary metabolites are didesmethylcitalopram, desmethylcitalopram, desmethylsertraline, and norfluoxetine.
  • SSRIs serotonin norepinephrine reuptake inhibitors
  • SNRIs selective serotonin norepinephrine reuptake inhibitors
  • Venlafaxine Venlafaxine has the following structure:
  • Structural analogs of venlafaxine are those compounds having the formula:
  • R 1 is hydrogen or alkyl
  • R 2 is C]-C 6 alkyl
  • R 4 is hydrogen, CpC 6 alkyl, formyl or alkanoyl
  • R 3 is hydrogen or CpC 6 alkyl
  • R 5 and R 6 are, independently, hydrogen, hydroxyl, C r C 6 alkyl, CpC 6 alkoxy, CpC 6 alkanoyloxy, cyano, nitro, alkylmercapto, amino, C 1 -C 6 alkylamino, dialkylamino, CpC 6 alkanamido, halo, trifluoromethyl or, taken together, methylenedioxy
  • n is 0, 1, 2, 3 or 4.
  • Duloxetine has the following structure:
  • Structural analogs of duloxetine are those compounds described by the formula disclosed in U.S. Patent No. 4,956,388 and in U.S. Patent No. 5,023,269 (see, for example, the formula at Col. 1, line 35 and the formula recited in Claim 1).
  • duloxetine analogs are: N-Methyl-3-(l-naphthalenyloxy)-3-(3- thienyl)-propanamine; N-Methyl-3-(2-naphthalenyloxy)-3-(cyclohexyl)- propanamine; N,N-Dimethyl-3-(4-chloro- 1 -naphthalenyloxy)-3-(3- furanyl)propanamine; N-Methyl-3-(5-methyl-2-naphthalenyloxy)-3-(2- thiazolyl)propanamine; N-Methyl-3-[3-(trifluoromethyl)- 1 -naphthalemyloxy]- 3-(3-methyl-2-thienyl)propanamine; N-Methyl-3-(6-iodo-l-naphthalenyloxy)- 3-(4-pyridyl)propanamine; N,N-Dimethyl-3-(l-n-
  • SSRJ analogs are l,2,3,4-tetrahydro-N-methyl-4-phenyl-l- naphthy lamine hydrochloride; 1 ,2,3 ,4-tetrahydro-N-methyl-4-pheny 1-(E)- 1 - naphthylamine hydrochloride; N,N-dimethyl- 1 -phenyl- 1 -phthalanpropylamine hydrochloride; gamma-(4-(trifluoromethyl)phenoxy)-benzenepropanamine hydrochloride; BP 554; CP 53261; O-desmethylvenlafaxine; WY 45,818; WY 45,881; N-(3-fluoropropyl)paroxetine; and Lu 19005.
  • Anticholinergic agents are compounds that reduce the effects mediated by acetylcholine at a receptor site, e.g., in the central nervous system or peripheral nervous system.
  • Anticholinergics include reversible competitive inhibitors of acetylcholine receptors, and are classified according to the receptors that are affected: antimuscarinic agents operate on the muscarinic acetylcholine receptors, and antinicotinic agents operate on the nicotinic acetylcholine receptors.
  • Anticholinergic agents may be used to treat neurodegenerative disorders.
  • Anticholinergic agents that may be suitable for use in the compositions, kits, and methods described herein include, e.g., atracurium; atropine; benztropine (e.g., benztropine mesylate); darifenacin; dicyclomine (e.g., dicyclomine hydrochloride); dimenhydrinate; diphenhydramine; doxacurium; ethopropazine (e.g., ethopropazine hydrochloride); flavoxate; ipratropium; mivacurium; oxybutynin; pancuronium; pirenzepine; scopolamine; solifenacin; suxamethonium (e.g., suxamethonium chloride); tiotropium; tolterodine (e.g., tolterodine tartrate); trihexyphenidyl (e.g., trihexyphenidyl hydrochloride); trime
  • Benztropine has the following structure:
  • Ethopropazine has the structure
  • each Xj and X 2 is selected from H, halogen, OH, CN, NO 2 , C 1-6 alkyl, or OCi -6 alkyl; n is 0, 1, 2, 3, 4, 5, or 6; and R 1 , R 2 , and R 3 are H or optionally substituted Ci -6 alkyl, or R 2 , and R 3 join to form a ring.
  • Trihexyphenidyl hydrochloride has the following structure:
  • Structural analogs of trihexyphenidyl are described by Formulas (I) and (II) in U.S. Patent No. 2,682,543 and by the general formula found in U.S. Patent No. 2,716,121. Structural analogs of trihexyphenidyl can also have the following structure
  • Ri, R 2 , R 3 , R 4 , and R 5 are H, halogen, OH, CN, NO 2 , C 1-6 alkyl, or OCi -6 alkyl; Ai and A 2 are H or optionally substituted Ci -6 alkyl, or A 1 and A 2 join together to form a ring; n is 1, 2, 3, 4, 5, or 6; and B 1 and B 2 are H or optionally substituted C 1-6 alkyl, or B] and B 2 join together to form a ring.
  • Estrogen modulators may be useful in the compositions, methods, and kits described herein.
  • Estrogen modulators include selective and non-selective estrogen receptor modulators, and further include estrogen-like compounds that modulate estrogen levels.
  • Estrogen modulators include estrogenic antagonists, e.g., antiestrogens, and estrogenic agonists.
  • Selective estrogen receptor modulators are high affinity ligands for estrogen receptors but can serve as either agonists or antagonists, depending on the tissue in which they act.
  • Exemplary estrogen modulators are acolbifene, afimoxifene, arzoxifene, clomifene (or clomiphene), N-desmethyltamoxifen, desmethylated arzoxifene, droloxifene, faslodex, 4'-fluoro- desmethylatedarzoxifene, fispemifene, fiilvestrant, 4-hydroxy tamoxifen, idoxifene, lasofoxifene, levormeloxifene, miproxifene, nafoxidine, ormeloxifene, ospemifene, pipendoxifene, raloxifene, tamoxifen, toremifene, trioxifene, CI-680, CI-628, CN-55,956-27, MER-25, U-11,555A, U-I l 5 IOOA, ICI-46
  • Clomiphene Clomiphene has the following structure:
  • Structural analogs of clomiphene include the other olefinic diastereomer of clomiphene. Structural analogs are also described by the general formula in U.S. Patent No. 2,914,563; the general formula of U.S. Patent No. 5,410,080; and in U.S. Patent No. 5,189,212.
  • Raloxifene has the following structure:
  • Exemplary structural analogs of raloxifene are LYl 17018 and LY317783. Analogs of raloxifene are also described by Formula (I) of U.S. Patent No. 5,610,167 and also in U.S. Patent Nos. 5,393,763; 5,457,117; 5,478,847; 5,811,120; 5,972,383; 6,458,811 ; 6,797,719; 6,894,064; 6,906,086; RE38,968; RE39,049; RE39,050; and RE39,708; and in WO2000037065.
  • Tamoxifen has the following structure:
  • Structural analogs of tamoxifen have the following structure:
  • Exemplary analogs of tamoxifen also include: 4-hydroxy tamoxifen; N- desmethyltamoxifen; threo- l-[4-(2,3-epoxypropoxy)-phenyl]- 1 ,2-diphenyl- 3,3,3-trifluoro-propane; (E)l-[4-(2,3-epoxypropoxy)-phenyl]-l,2-diphenyl- 3,3,3-trifluoro-propene; (E)-l,2-diphenyl-3,3,3-trifluoro-l-[4-(2-[bis-(2- hydroxyethyl)-amino]-eth oxy)-phenyl)]-propene: (E)-l,2-diphenyl-3,3,3- trifluoro- 1 -[4-(2-[4-methylpiperazino]-ethoxy)-phenyl]-propene; 1 -[4-(2- dimethy
  • Toremifene has the following structure:
  • IKK- ⁇ inhibitors are described by: Formulas (I), (II), (III), and (IV) in U.S. Patent Nos. 5,939,421 and 6,150,372; Formulas (I) and (II) in U.S. Patent Nos. 6,627,637 and 7,026,331; Formulas (I) and (If) and Compound 6 in WO2002060386 and U.S. Patent No. 6,869,956; Formula (I) and (If) in U.S.
  • IKK- ⁇ inhibitors include but are not limited to: MLN0415 ;
  • IMD-0354 is an IKK- ⁇ inhibitor and has the following structure:
  • Analogs of IMD-0354 include other small molecule NF- ⁇ B inhibitors.
  • Exemplary small molecule NF- ⁇ B inhibitors are: antioxidants; SP 100030; dehydroxymethylepoxyquinomicin (DHMEQ); Formula (I) in WO2006/032322, hereby incorporated by reference.
  • Analogs of IMD-0354 are also described by the following formula
  • X is halogen at any position of the ring; X is O or X; R 1 , R 2 , R 3 , R 4 , and R 5 are H or perhalogenated C 1-6 alkyl; and R 6 is H or Ci -6 alkyl.
  • Alverine has the following structure:
  • R 1 is H or C 1-6 alkyl
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Rj 0 , and R n are selected from H, halogen, OH, C 1-6 alkyl, and OC 1-6 alkyl
  • m is 0, 1, 2, 3, 4, 5, or 6
  • n is 0, 1, 2, 3, 4, 5 or6.
  • Amiodarone has the following structure:
  • Structural analogs of amiodarone are described by the general formula and Examples I, II, and III found in U.S. Patent No. 3,248,401; the general formula in U.S. Patent No. 5,849,788 (see, for example, claim 1); the compounds disclosed in U.S. Patent No. 5,567,728; and Formula (I) in U.S. Patent No. 4,851,554. Additional analogs of amiodarone are found in U.S. Patent Nos. 7,148,240; 6,515,147; 6,316,487; and 5,981,514.
  • Exemplary structural analogs of amiodarone are: 3,5-diiodo-4-(2-N,N- diethylaminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride; 2- methyl-3-(3,5-diiodo-4-(2-N,N-diethylamino-ethoxy)-benzoyl)benzofuran hydrochloride; 2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy- benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran; 4'-hydroxy-3'- iodo-3,5 diiodo-4-(2-N,N-dimethylamino-ethoxy)benzophenone hydroch
  • Chloroquine has the following structure:
  • Hydroxychloroquine has the following structure:
  • Ri, R 2 , R 3 , R 4 , and R 5 are selected from H, halogen, Ci -6 alkyl, OH, OCi -6 alkyl, CN, or NO 2 ;
  • A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive;
  • R 6 , R 7 , Rg, and R 9 are H, Ci -6 alkyl, or (CH 2 ) n (CH 2 OH) where n is 0, 1, 2, 3, 4, or 5.
  • Chlorprothixene has the following structure:
  • Structural analogs of chlorprothixene have the following structure: wherein, independently, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Rs, and R 9 , are each selected from H, halogen, C 1-6 alkyl, perhalogenated Ci -6 alkyl, OH, OC 1-6 alkyl, OCF 3 , SH, SCi -6 alkyl, or SCF 3 , wherein at least one OfR 1 -R 8 is a halogen; Y is CH 2 , O, NH, S(O) 0-2 , (CH 2 ) 3 , (CH) 2 , CH 2 O, CH 2 NH, CHN, or CH 2 S; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; Bi and B 2 are selected from H, perhalogenated C 1-6 alkyl, C 1-6 alkyl, or Bi and B 2 join
  • Dicyclomine has the following structure:
  • Structural analogs of dicyclomine are described in U.S. Patent No. 2,474,796. Structural analogs of dicyclomine are also described by the following formula
  • n 1, 2, 3, 4, 5 ,or 6
  • X and Y are selected from O and S
  • Ri and R 2 are H or Ci -6 alkyl.
  • Hexachlorophene has the following structure:
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are H or halogen and n is O, 1, 2, 3, 4, or 5.
  • Nitazoxanide has the following structure:
  • Structural analogs of nitazoxanide include tizoxanide or have the following structure:
  • R 1 and R 2 are selected from H, halogen, CN, NO 2 , CF 3 , or Ci -6 alkyl;
  • R 3 is H or Ci -6 alkyl;
  • R 4 , R 5 , R 6 , R 7 , and R 8 are selected from H, halogen, CN, NO 2 , CF 3 , Ci -6 alkyl, or OCj -6 alkyl;
  • X, Y, and Z is selected from O, S, or NR 9 ;
  • A is a bond, O, S, or NR 9 ;
  • R 9 is H or Ci -6 alkyl; and
  • B is H or C(Z)-X-R 8 .
  • Thioridazine has the following structure:
  • Structural analogs of thioridazine have the structure wherein, independently, Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and Rg are each selected from H, halogen, C 1-6 alkyl, perhalogenated Ci -6 alkyl, OH, OCi -6 alkyl, OCF 3 , SH, SC, -6 alkyl, or SCF 3 ; Y is CH 2 , O, NH, S(O) 0-2 , (CH 2 ) 3 , (CH) 2 , CH 2 O, CH 2 NH, CHN, or CH 2 S; A is a bond or a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; each Bi, B 2 , B 3 , and B 4 is, independently, H, halogen, perhalogenated Ci -6 alkyl, Ci -6 alkyl, OCi -6 alkyl, O(per
  • Thioridazine analogs are also described by Formulas (I), (IIA), and (IIB) in U.S. Application Publication No. 2007-0287702.
  • Vanoxerine has the structure:
  • therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective for such therapeutic agents.
  • Agents that may be particularly useful include those that prevent or slow the rate of neural deterioration or death, or those that treat, prevent, or ameliorate one or more symptoms of a neurodegenerative disorder.
  • Exemplary therapeutic classes and agents are listed in Table 2. Combinations of the classes and agents of Table 2 may also be used. If more than one agent is employed, therapeutic agents may be delivered separately or may be admixed into a single formulation. When agents are present in different pharmaceutical compositions, different routes of administration may be employed.
  • Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (e.g., intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration).
  • agents may be administered by intracranial, intrathecal, or epidural administration. Any method of administration that bypasses the blood-brain barrier or enhances its permeability (e.g., administration of a NaVCa + * exchange blocker, mannitol, or Cereport) may be useful.
  • an agent and additional therapeutic agents are administered at least one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days apart.
  • the dosage and frequency of administration of each component of the combination can be controlled independently. For example, one compound may be administered three times per day, while the second compound may be administered once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the therapeutic agents may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions described herein to a patient.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds, described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • the additional therapeutic regimen may involve other therapies, e.g., transplantation of neural cells (including, if needed, anti-inflammatory and/or immunosuppressive therapy), or a modification to the lifestyle of the patient being treated.
  • therapies e.g., transplantation of neural cells (including, if needed, anti-inflammatory and/or immunosuppressive therapy), or a modification to the lifestyle of the patient being treated.
  • the drugs used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula I.
  • (A) is an agent listed in Table Ia or Ib covalently tethered via a linker (L) to (B), any agent of the classes and agents listed in Tables Ia, Ib, and 2.
  • Conjugates can be administered to a subject by any route and for the treatment of any disease described herein.
  • the conjugates can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases).
  • the conjugates can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate.
  • Conjugates can be prepared using techniques familiar to those skilled in the art.
  • the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996.
  • the synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B).
  • commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m- nitrophenyl.
  • amides such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert- butylsulfonyl amides.
  • protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2- (trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho- esters, and halo-esters.
  • Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P- nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy- trityls), and silyl ethers.
  • Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls.
  • sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides).
  • Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule.
  • the conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (2 nd Ed.), John Wiley & Sons, 1991 and PJ. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
  • the linker component is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
  • linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B).
  • functional groups located on drug (A) and drug (B).
  • chemically reactive functional groups include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
  • the covalent linking of drug (A) and drug (B) may be effected using a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an amide linking the two.
  • N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions.
  • Reagents such as 2- iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
  • reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents.
  • Representative alkylating agents include:
  • N-maleimide derivatives which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group, for example, as described by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J. 91 :589 (1964);
  • aryl halides such as reactive nitrohaloaromatic compounds;
  • epoxide derivatives such as epichlorohydrin and bisoxiranes, which may react with amino, sulfhydryl, or phenolic hydroxyl groups;
  • Representative amino-reactive acylating agents include: (i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives respectively;
  • acylazides e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal. Biochem. 58:347 (1974); and (viii) imidoesters, which form stable amidines on reaction with amino groups, for example, as described by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962).
  • Aldehydes and ketones may be reacted with amines to form Schiff s bases, which may advantageously be stabilized through reductive amination.
  • Alkoxylamino moieties readily react with ketones and aldehydes to produce stable alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1 :96 (1990).
  • reactive moieties capable of reaction with carboxyl groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv. Protein Chem. 3:169 (1947).
  • Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed. It will be appreciated that functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity.
  • Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as ⁇ -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2- bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
  • So-called zero-length linkers involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used.
  • the linker will include two or more reactive moieties, as described above, connected by a spacer element.
  • the presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two.
  • the reactive moieties in a linker may be the same (homobifunctional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
  • Spacer elements in the linker typically consist of linear or branched chains and may include a C 1 -Ci 0 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 6 heterocyclyl, C 6 -C] 2 aryl, C 7 -C 14 alkaryl, C 3 -Ci 0 alkheterocyclyl, or C 1 -C 10 heteroalkyl.
  • the linker is described by formula (II):
  • G 1 is a bond between drug (A) and the linker;
  • G 2 is a bond between the linker and drug (B);
  • Z 1 , Z 2 , Z 3 , and Z 4 each, independently, is selected from O, S, and NR 31 ;
  • R 31 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 2 -C 6 heterocyclyl, C 6 -C 12 aryl, C 7 -C 14 alkaryl, C 3 -C 10 alkheterocyclyl, or C 1 -C 7 heteroalkyl;
  • R 30 is a C 1 -C 10 alkyl, C 2
  • homobifunctional linkers useful in the preparation of conjugates include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol.
  • diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol.
  • any of the agents described herein may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
  • each agent may be formulated in a variety of ways that are known in the art. Desirably, the agents are formulated together for the simultaneous or near simultaneous administration of the agents. Such co-formulated compositions can include the two agents formulated together in the same pill, capsule, liquid, etc. It is to be understood that, when referring to the formulation of such combinations, the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations described herein. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be suitably matched.
  • kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc.
  • the kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
  • the unit dose kit can contain instructions for preparation and administration of the compositions.
  • the kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging").
  • the kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.
  • BBB blood-brain barrier
  • Craniotomy a procedure known in the art, can be used with any composition described herein for delivery to the brain.
  • an opening is made in the patient's cranium, and a compound is delivered via a catheter.
  • This approach can be used to target a compound to a specific area of the brain.
  • Intrathecal administration provides another means of bypassing the BBB for drug delivery.
  • drugs are administered to the spinal chord, for example, via lumbar puncture or through the use of devices such as pumps.
  • Lumbar puncture may be used for single or infrequent administration, whereas constant and/or chronic administration may be achieved using any commercially available pump attached to a intraspinal catheter, e.g., a pump and catheter made by Medtronic (Minneapolis, Minn.).
  • a pump and catheter made by Medtronic (Minneapolis, Minn.).
  • compositions described herein can be administered along with a compound or compounds that induce a transient increase in permeability of the BBB.
  • Such compounds include mannitol, Cereport (RMP-7), and KB-R7943, a Na + ZCa 4"1" exchange blocker.
  • Compounds described herein can be modified (e.g., lipidated or acetylated) to increase transport across the BBB following systemic administration (e.g., parenteral) by using chemical modifications that are standard in the art.
  • compounds described herein are conjugated to peptide vectors that are transported across the BBB.
  • compounds may be conjugated to a monoclonal antibody to the human insulin receptor as described by Partridge (Jpn. J. Pharmacol. 87:97- 103, 2001), thus permitting the compound to be transported across the BBB following systemic administration.
  • Compounds described herein can be conjugated to such peptide vectors, for example, using biotin-streptavidin technology.
  • the dosage of any of the agents of the combinations described herein will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2,000 mg per day, about 1 mg to 1,000 mg per day, or about 5 mg to 500 mg per day.
  • Administration of each drug in the combination can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. Additional Applications
  • compounds may be employed in mechanistic assays to determine whether other combinations, or single agents, are as effective as the combination in treating, preventing, or ameliorating neurodegenerative disorders (e.g., HD or any of its associated conditions) using assays generally known in the art, examples of which are described herein.
  • candidate compounds may be tested, alone or in combination with one or more compounds selected independently from any of the agents of Tables Ia and Ib, and applied to cells, e.g., neural cells or mouse striatal knock-in cell line STHdhQ 111 expressing a toxic mutant polyglutamine repeat protein. After a suitable time, these cells are examined for immunoreactivity using the polyQ antibody, 1F8. A decrease in perinuclear staining, in comparison to control cells not treated with the candidate compound, identifies a candidate compound or combination of agents as an effective agent to treat, prevent, or ameliorate a neurodegenerative disorder.
  • the agents described herein may also be useful tools in elucidating mechanistic information about the biological pathways involved in neural cell deterioration and death. Such information can lead to the development of new combinations or single agents for treating, preventing, or ameliorating neurodegenerative disorders.
  • Methods known in the art to determine biological pathways can be used to determine the pathway, or network of pathways, affected by contacting cells, e.g., neural cells, with the compounds described herein. Such methods can include analyzing cellular constituents that are expressed or repressed after contact with the compounds described herein as compared to untreated, positive or negative control compounds, and/or new single agents and combinations, or analyzing some other activity of the cell such as enzyme activity, nutrient uptake, and proliferation.
  • Cellular components analyzed can include gene transcripts and protein expression.
  • Suitable methods can include standard biochemistry techniques, radiolabeling the compounds described herein (e.g., 14 C or ⁇ labeling), and observing the compounds binding to proteins, e.g. using 2D gels, gene expression profiling. Once identified, such compounds can be used in in vivo models to further validate the tool or develop new agents or strategies to treat, prevent, or ameliorate neurodegenerative disorders.
  • the methods described herein may also be used prophylactically, in patients who are at an increased risk of developing a neurodegenerative disorder, e.g., HD, or a condition associated with such a disorder.
  • a neurodegenerative disorder e.g., HD
  • Risk factors include, for example, age, family history of neurodegenerative disorders, and psychological or psychiatric profile.
  • Peptides, peptide mimetics, and peptide fragments may be suitable for use.
  • exemplary compounds include those that reduce the amount of target protein or RNA levels (e.g., antisense compounds, dsRNA, ribozymes) and compounds that compete with endogenous mitotic kinesins or protein tyrosine phosphatases for binding partners (e.g., dominant negative proteins or polynucleotides encoding the same).
  • RNA secondary structure folding program such as MFOLD (M. Zuker, D. H. Mathews & D. H. Turner, Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO ASI Series, Kluwer Academic Publishers, (1999)).
  • Sub-optimal folds with a free energy value within 5% of the predicted most stable fold of the mRNA are predicted using a window of 200 bases within which a residue can find a complimentary base to form a base pair bond. Open regions that do not form a base pair are summed together with each suboptimal fold and areas that are predicted as open are considered more accessible to the binding to antisense nucleobase oligomers.
  • Other methods for antisense design are described, for example, in U.S. Patent No. 6,472,521, Antisense Nucleic Acid Drug Dev. 1997 7:439-444, Nucleic Acids Research 28:2597-2604, 2000, and Nucleic Acids Research 31 :4989-4994, 2003.
  • RNA Interference The biological activity of a target molecule can be reduced through the use of RNA interference (RNAi), employing, e.g., a double stranded RNA (dsRNA) or small interfering RNA (siRNA) directed to the target molecule in question (see, e.g., Miyamoto et al., Prog. Cell Cycle Res. 5:349-360, 2003; U.S. Patent Application Publication No. 20030157030).
  • dsRNA double stranded RNA
  • siRNA small interfering RNA
  • Methods for designing such interfering RNAs are known in the art. For example, software for designing interfering RNA is available from Oligoengine (Seattle, WA).
  • Example 1 Screening Assays Provided are screening methods for identifying candidate compounds that treat, prevent, or ameliorate neurodegenerative disorders, e.g., HD.
  • Htt a variety of model systems, including cellular as well as animal models, have demonstrated that the exon 1 portion of Htt, containing an expanded polyglutamine region, is sufficient to cause pathology.
  • STHdhQl 11 cell line derived from the HD knock-in mouse model which expresses mutant Htt at endogenous level with the right genetic context, has been widely used and well characterized. This cell line recapitulates many HD pathogenic features, such as mitochdria dysfunction and energy deficiency, and thus is regarded as one of the most HD-relevant cellular models.
  • HCS high content screening
  • % of inhibition [(DMSO treated-compound treated)/DMSO treated] 100 More than 50% of killing was consistently achieved 72 hours following hexachlorophene treatment when comparing with DMSO-treated wells.
  • Single agent curve data were used to define a dilution series for each compound to be used for combination screening in a 6x6 matrix format.
  • a dilution factor f of 2, 3, or 4, depending on the sigmoidicity of the single agent curve, five dose levels were chosen with the central concentration close to the fitted EC 50 .
  • a dilution factor of 4 was used, starting from the highest achievable concentration.
  • Combination effects can be most readily characterized by comparing each data point's inhibition to that of a combination reference model that was derived from the single agent curves.
  • HSA highest single agent
  • Loewe additivity is a generally accepted reference for synergy, as it represents the combination response generated if X and Y are the same compound. / HSA is easily calculated from / X)Y , but determining / Loewe requires interpolation and numerical root finding.
  • the automated analysis first determined plates to be verified, rejected or undetermined. All plates were then evaluated manually on a plate-by-plate basis and, if necessary, assigned a status of hand accepted or rejected. Additionally, individual blocks of data on verified plates could be manually marked for exclusion.
  • the quality control criterion for automated analysis was called the Z'- factor, which is defined as:
  • SD represents standard deviation
  • DMSO represents vehicle treated
  • Control represents the background which is defined by wells undergoing all the assay procedures but without the secondary antibody.
  • any cell line expressing a CAG repeat gene containing an expanded CAG repeat region may be used.
  • Screening assays directed to a given polyglutamine repeat disorder may be varied, e.g., by utilizing a cell line expressing a polyglutamine repeat protein, or fragment thereof, associated with that disorder. Any cutoff for hit picking may be chosen, e.g., 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • any method of assaying cell viability may be employed.
  • Example 2 Further Screening Assay: Protocol for TMRE Assay Using Mouse Striatal Cell Lines
  • the protocol for the screening method is provided below.
  • FCCP FCCP stock: 50 ⁇ M in DMSO

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Abstract

Provided are compositions, kits, and methods for treating, preventing, and ameliorating neurodegenerative disorders, e.g., Huntington's disease.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS
Background of the Invention In general, this invention relates to the treatment, prevention, and amelioration of neurodegenerative disorders, e.g., Huntington's disease, and symptoms thereof.
Neurodegenerative disorders affect millions of individuals. One class of these disorders, the polyglutamine expansion disorders, is characterized by the presence of an expanded CAG repeat region within the coding sequence of a gene. While the threshold length of the CAG expansion is variable in these disorders, longer repeat length generally results in an earlier onset of the disease. For Huntington's disease, the threshold CAG repeat length for the onset of the disease is generally regarded as greater than 38 CAGs, resulting in a polyglutamine domain proximal to the N-terminus of the Huntingtin protein.
Huntington's disease (HD), one of at least nine known inherited polyglutamine expansion disorders, affects men and women with equal frequency, about 5-10 per 100,000. It can be characterized by five hallmark features: heritability; chorea; behavioral or psychiatric disturbances; cognitive impairment (dementia); and late-onset, with death occurring 15-20 years post- onset of motor dysfunctions. In most patients, the onset of the disease occurs in the third to fifth decade of life.
HD is an autosomal dominant disorder with a gene mutation on chromosome 4. This gene encodes a large protein, huntingtin (Htt), with multiple important functions. HD is caused by an expansion of the CAG repeat in the huntingtin (htt) gene, resulting in an expanded polyglutamine (poly Q) region near the N-terminus of Htt. Although the disease progression in HD is accompanied by widespread loss of neurons in the brain, the pathology is seen earliest in the striatum, in particular the medium spiny neurons, and to a lesser extent in the cerebral cortex.
The pathologic mechanisms underlying HD are not yet completely understood. Leading hypotheses include excitotoxicity, mitochondrial dysfunction, deficiencies in ubiquitin-mediated proteolysis, protease-dependent accumulation of poly-glutamine protein fragments, formation of cytosolic and nuclear inclusions, changes in gene expression, and neuronal cell degeneration and death. Although the mode of neuronal cell death continues to be debated, considerable evidence suggests that apoptosis plays an important role. There are no current HD therapies, although some patients treat their symptoms with conventional neuroleptics to decrease chorea, and psychotropic medications to address depression, obsessive compulsive symptoms, or psychosis. There are currently no effective therapies for preventing the onset or slowing the progression of HD. Thus, there is a need to develop effective new therapies for treating, preventing, or ameliorating HD and other neurodegenerative disorders.
Summary of the Invention
Provided are compositions, methods, and kits for treating, preventing, and ameliorating neurodegenerative disorders. The compositions, methods, and kits described herein may be useful for treating patients having or at risk of having a polyglutamine expansion disorder, such as HD. The compositions, methods, and kits described herein also may be useful for treating symptoms or complications associated with neurodegenerative disorders, e.g., chorea, depression, obsessive-compulsive behavior, psychosis, dystonia (e.g., jaw clenching), and behavioral disturbances.
Accordingly, provided is a composition that includes one or more first agents selected independently from the agents of Tables Ia and Ib, and one or more second, different agents selected independently from the classes and agents of Tables Ia, Ib, and 2. The agent or agents of Tables Ia and Ib can be, e.g., tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, selective serotonin reuptake inhibitors ("SSRIs"), anticholinergics, IKK-β inhibitors, or estrogen modulators. In certain embodiments, the first and second agents are selected from a single row of Tables 3a and 3b. In some instances, the first agent and second agent are present in amounts that, when administered to a patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder, e.g., a disorder selected from the group consisting of a polyglutamine expansion disorder (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), another trinucleotide repeat expansion disorder (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt- Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, Steele-Richardson-Olszewski disease, and Tabes dorsalis. The composition may be formulated for any route of administration, e.g., oral, systemic, intracranial, intrathecal, or epidural administration.
Also provided is a composition consisting of active ingredients and pharmaceutically acceptable carriers, wherein the active ingredients consist of a first agent selected independently from the agents of Tables Ia and Ib, and a second, different agent selected independently from the classes and agents of Tables Ia, Ib, and 2. In certain embodiments, the first and second agents are selected from a single row of Tables 3a and 3b.
Also provided is a method for treating, preventing, or ameliorating a neurodegenerative disorder by administering to a patient one or more agents selected independently from any of the agents of Tables Ia and Ib in an amount sufficient to treat, prevent, or ameliorate the neurodegenerative disorder.
Also provided is a method for treating, preventing, or ameliorating a neurodegenerative disorder by administering to a patient one or more agents selected independently from the agents of Table Ib and one or more different agents selected independently from the classes and agents of Table 2 in amounts sufficient to treat, prevent, or ameliorate the neurodegenerative disorder.
Also provided is a method for treating, preventing, or ameliorating a neurodegenerative disorder by administering to a patient at least two different agents selected independently from any of the agents of Tables Ia and Ib, wherein the first and second agents are administered simultaneously or within 28 days of each other, in amounts that together are sufficient to treat, prevent, or ameliorate the neurodegenerative disorder. In certain embodiments, the first and second agents are selected from a single row of Tables 3a and 3b. The first and second agents may be administered simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days of each other.
In some instances, in the methods described herein, the agent or agents administered to the patient, e.g., tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, SSRIs, anticholinergics, IKK-β inhibitors, or estrogen modulators, may reduce the rate of neuronal death in the patient (e.g., a human) relative to the rate of neuronal death in a control. In addition, the methods may include an additional therapeutic regimen. For example, the additional therapeutic regimen may include administering to the patient an additional therapeutic agent, such that the agent or agents selected from Tables Ia and Ib and the additional therapeutic agent are present in amounts that, when administered to the patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder. The additional therapeutic agent may be, e.g., selected from the classes and agents of Table 2. The agent or agents from Tables Ia or Ib and the additional therapeutic agent may be administered simultaneously or within one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days of each other, via any route of administration.
Also provided is a kit that includes an agent selected from the agents of Tables Ia and Ib and instructions for administering the agent to a patient having or at risk of having a neurodegenerative disorder. Optionally, the kit includes two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib that may, but need not be, admixed in the same composition. This kit may also include instructions for administering the additional agent or agents, or the admixed composition, to the patient.
Also provided is a kit that includes one, two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib and one or more agents selected independently from the classes and agents of Table 2. The agents may, but need not, be admixed in the same composition. The kit also includes instructions for administering these agents to a patient having or at risk of having a neurodegenerative disorder.
Also provided is a kit that includes either one, two, three, four, or more than four agents selected independently from the agents of Tables Ia and Ib, or one or more agents selected independently from the classes and agents of Table 2. The kit also includes instructions for administering these agents together to a patient having or at risk of having a neurodegenerative disorder. In any of the kits described herein, two agents may be selected from a single row of Tables 3a and 3b.
Also provided is a method of identifying a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder, including the steps of: (a) providing cells that include a gene encoding a polyglutamine repeat polypeptide, such that the polypeptide includes an expanded polyglutamine repeat region relative to a wild-type polyglutamine repeat polypeptide; (b) inducing expression of the gene; (c) contacting the cells with an agent selected from the agents of Tables Ia and Ib and a candidate compound; and (d) determining whether the combination of the agent and the candidate compound reduces perinuclear staining by a polyQ antibody, e.g., 1F8, relative to cells contacted with the agent but not contacted with the candidate compound, wherein a reduction in perinuclear staining (as determined, e.g., by immunocytochemistry (ICC) analysis) identifies the combination as a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder. The polyglutamine repeat polypeptide that includes the expanded polyglutamine repeat region may include, e.g., full-length Htt Ql 11, or another variant of a polypeptide associated with a polyglutamine expansion disorder. The method may use, e.g., mammalian cells, e.g., mouse striatal cells, e.g., STHdhQl 11 cells derived from knock- in mice.
Table Ia
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Table Ib
Figure imgf000011_0001
Table 2
Figure imgf000012_0001
Table 3a
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Table 3b
Figure imgf000018_0001
By "an amount sufficient" is meant the amount of a compound, alone or in combination with another therapeutic regimen, required to treat, prevent, or ameliorate a neurodegenerative disorder, such as HD, in a clinically relevant manner. A sufficient amount of an active compound used for therapeutic treatment of neurodegenerative disorders varies depending upon the manner of administration, age, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of compound in the combination that is safe and efficacious in the treatment of a patient having a neurodegenerative disorder, such as HD, over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug
Administration).
By "candidate compound" is meant a chemical, be it naturally-occurring or artificially-derived. Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof.
Compounds include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein. Compounds may also be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36Cl). Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non- isotopically-labeled reagent.
By "expanded polyglutamine repeat region" is meant a region of a polyglutamine repeat polypeptide in which the number of glutamine residues is greater than the number of glutamine residues in a corresponding wild-type polypeptide. An exemplary polypeptide containing an expanded polyglutamine repeat region is, e.g., full-length HttQl 11, which contains a region of 111 glutamine residues. An expanded polyglutamine repeat region contains greater than, e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or even 100 glutamine residues. Alternatively, an expanded polyglutamine repeat region contains greater than, e.g., 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or even 100 more glutamine residues than the number of glutamine residues in a corresponding wild-type polypeptide. By a "high dosage" is meant at least 5% more (e.g., at least 10%, 20%, 50%, 100%, 200%, or even 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition. For example, a high dosage of an agent that prevents or slows the rate of neural deterioration or death associated with a neurodegenerative disorder and that is formulated for intravenous administration may differ from a high dosage of the same agent formulated for oral administration.
By a "low dosage" is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any human disease or condition.
By "neurodegenerative disorder" is meant any disease or disorder caused by or associated with the deterioration of cells or tissues of the nervous system. Exemplary neurodegenerative disorders are polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)), other trinucleotide repeat expansion disorders (e.g., fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, myotonic dystrophy, spinocerebellar ataxia type 8, and spinocerebellar ataxia type 12), Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also referred to as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, ischemia stroke, Krabbe disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, Steele- Richardson-Olszewski disease, and Tabes dorsalis.
By "patient" is meant any animal, e.g., a mammal (e.g., a human). Other animals that can be treated using the methods, compositions, and kits described herein include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
A patient who is being treated for a neurodegenerative disorder, e.g., HD, is one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means, such as those described herein. A patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis. One in the art will understand that patients may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors, such as age, family history of neurodegenerative disorders, and psychological or psychiatric profile. By "polyglutamine repeat polypeptide" is meant any polypeptide containing at least five consecutive glutamine residues. Exemplary polyglutamine repeat polypeptides are those associated with polyglutamine expansion disorders (e.g., HD, dentatorubropallidoluysian atrophy, Kennedy's disease (also referred to as spinobulbar muscular atrophy), and spinocerebellar ataxia (e.g., type 1, type 2, type 3 (also referred to as Machado- Joseph disease), type 6, type 7, and type 17)). For example, Htt, which is associated with HD, is a polyglutamine repeat polypeptide.
The terms "polypeptide" and "peptide" are used interchangeably and refer to any chain of more than two natural or unnatural amino acids, regardless of post-translational modification (e.g., glycosylation or phosphorylation), constituting all or part of a naturally-occurring or non-naturally occurring polypeptide or peptide, as is described herein. As used herein, a natural amino acid is a natural α-amino acid having the L-confϊguration, such as those normally occurring in natural proteins. Unnatural amino acid refers to an amino acid, which normally does not occur in proteins, e.g., an epimer of a natural α-amino acid having the L configuration, that is to say an amino acid having the unnatural D- configuration; or a (D,L)-isomeric mixture thereof; or a homologue of such an amino acid, for example, a β-amino acid, an α,α-disubstituted amino acid, or an α-amino acid wherein the amino acid side chain has been shortened by one or two methylene groups or lengthened to up to 10 carbon atoms, such as an α- amino alkanoic acid with 5 up to and including 10 carbon atoms in a linear chain, an unsubstituted or substituted aromatic (α-aryl or α-aryl lower alkyl), for example, a substituted phenylalanine or phenylglycine.
By "systemic administration" is meant any nondermal route of administration, and specifically excludes topical and transdermal routes of administration.
By "treating, preventing, or ameliorating a neurodegenerative disorder" is meant ameliorating such a condition before or after its onset. As compared with an equivalent untreated control, such amelioration or degree of prevention is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
In the generic descriptions of compounds described herein, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 6 carbon atoms or Ci-C6 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 6 carbon atoms includes each Of C1, C2, C3, C4, C5, and C6. A CpCi2 heteroalkyl, for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.
As used herein, the terms "alkyl" and the prefix "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and, in some embodiments, have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
By "C1-C6 alkyl" is meant a branched or unbranched hydrocarbon group having from 1 to 6 carbon atoms. A C1-C6 alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C1-C6 alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.
By "C2-C6 alkenyl" is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms. A C2-C6 alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The C2-C6 alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C2-C6 alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-l-ethenyl, 1-propenyl, 1- butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1-propenyl, and 2-methyl-2-propenyl.
By "C2-C6 alkynyl" is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms. A C2-C6 alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C2- C6 alkynyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C2-C6 alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, and 3-butynyl.
By "C2-C6 heterocyclyl" is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle may optionally be quaternized. In some embodiments, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, lH-indazole, 2-pyrrolidonyl, 2H,6H-l,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH- carbazole, 4H-quinolizinyl, 6H-l,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, dmydrofuro[2,3-b]tetrahydrofuran, furanyl, fiirazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, moφholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5- triazolyl, 1,3,4-triazolyl, xanthenyl. In some embodiments, 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, IH- indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. In some embodiments, 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
By "C6-Ci2 aryl" is meant an aromatic group having a ring system comprised of carbon atoms with conjugated π electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
By "C7-Ci4 alkaryl" is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms. By "C3-Ci0 alkheterocyclyl" is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2- tetrahydrofuranylmethyl).
By "Ci-C7 heteroalkyl" is meant a branched or unbranched alkyl, alkenyl, or alkyny 1 group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
Examples Of Ci-C7 heteroalkyls include, without limitation, methoxymethyl and ethoxy ethyl.
By "halogen" is meant bromine, chlorine, iodine, or fluorine. By "fluoroalkyl" is meant an alkyl group that is substituted with a fluorine atom.
By "perfluoroalkyl" is meant an alkyl group consisting of only carbon and fluorine atoms. By "carboxyalkyl" is meant a chemical moiety with the formula
-(R)-COOH, wherein R is selected from C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 heterocyclyl, C6-C12 aryl, C7-C14 alkaryl, C3-Cj0 alkheterocyclyl, and C1-C7 heteroalkyl.
By "hydroxyalkyl" is meant a chemical moiety with the formula -(R)- OH, wherein R is selected from C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2- C6 heterocyclyl, C6-Ci2 aryl, C7-C14 alkaryl, C3-C10 alkheterocyclyl, and C1-C7 heteroalkyl.
By "alkoxy" is meant a chemical substituent of the formula -OR, wherein R is selected from CpC7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 heterocyclyl, C6-Ci2 aryl, C7-C14 alkaryl, C3-C10 alkheterocyclyl, and Ci-C7 heteroalkyl.
By "aryloxy" is meant a chemical substituent of the formula -OR, wherein R is a C6-C12 aryl group.
By "alkylthio" is meant a chemical substituent of the formula -SR, wherein R is selected from Ci -C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C6 heterocyclyl, C6-Ci2 aryl, C7-Ci4 alkaryl, C3-C]0 alkheterocyclyl, and C1-C7 heteroalkyl.
By "arylthio" is meant a chemical substituent of the formula -SR, wherein R is a C6-Ci2 aryl group. By "quaternary amino" is meant a chemical substituent of the formula
-(R)-N(R')(R")(R"')+, wherein R, R', R", and R'" are each independently an alkyl, alkenyl, alkynyl, or aryl group. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety. The nitrogen atom, N, is covalently attached to four carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom.
Other features and advantages of the invention will be apparent from the detailed description and from the claims.
Detailed Description of the Invention
Provided are compounds that, alone or in combination, may be effective in the treatment, prevention, or amelioration of neurodegenerative disorders. The compositions, methods, and kits described herein may be useful for treating patients having or at risk of having a polyglutamine expansion disorder, e.g., HD. Accordingly, a patient that has been diagnosed with or is at risk of having a neurodegenerative disorder is administered one, two, three, four, or more agents selected independently from any of the agents of Tables Ia and Ib. Optionally, analogs of these agents may be employed. In the case of a polyglutamine expansion disorder, for example, such administration may prevent or slow the rate of neural deterioration or death. The ability of the agent to prevent or slow the rate of neural deterioration or death may be attributed, for example, to its ability to inhibit the disease-causing activity of a mutant polyglutamine protein, e.g., Htt. Optionally, the patient may also receive other therapeutic regimens.
In one particular example, the patient being treated is administered two agents selected independently from any of the agents of Tables Ia and Ib within 28 days of each other in amounts that together are sufficient to treat, prevent, or ameliorate the neurodegenerative disorder. The two agents are desirably administered within 14 days of each other, more desirably within seven days of each other, and even more desirably within twenty- four hours of each other, or even simultaneously. If desired, either one of the two agents may be administered in low dosage. Diagnosis of Neurodegenerative Disorders
The methods and compositions described herein may be useful for treating any patient that has been diagnosed with or is at risk of having a neurodegenerative disorder, such as HD. A patient in whom the development of a neurodegenerative disorder is being prevented may or may not have received such a diagnosis. One skilled in the art will understand that a patient may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors. Diagnosis of neurodegenerative disorders, e.g., HD, may be performed using any standard method known in the art, such as those described herein. Methods for diagnosing such disorders are described, for example, in U.S. Patent Nos. 6,355,481 and 6,210,970. HD may be diagnosed and monitored, for example, by performing genetic tests (e.g., by sequencing the htt gene and testing for the presence of an expanded CAG repeat region); neurological examination, e.g., testing body movement, reflexes, eye movement, hearing, or balance, and/or performing brain imaging; evaluating family history of disease; or conducting a psychological or psychiatric interview. Symptoms or altered behavior that can lead to a diagnosis of HD include, e.g., aggression, altered sexuality, anxiety, apathy, delusions, denial, depression, disinhibition, frustration, hallucinations, irritability, mania, repetition, and lack of awareness. A patient may be diagnosed as having or being at risk of having HD if a genetic test is performed and the number of CAG repeats in the htt gene is greater than a threshold number, e.g., 38. A larger number of repeats is generally associated with an earlier onset of disease. Similar diagnostic methods may be used, e.g., for any of the polyglutamine expansion disorders. In addition, genetic, neurological, and/or behavioral testing may be used to diagnose other neurodegenerative disorders. Therapeutic Agents
An effective amount of one, two, three, four, or more agents selected independently from any of the agents of Tables Ia and Ib may be administered to a patient having, or being at risk of having, a neurodegenerative disorder, thereby treating, preventing, or ameliorating such a disorder.
In the case of HD, for example, an agent described herein may inhibit the disease-causing activity of a mutant Htt protein, e.g., by preventing or reducing Htt aggregation.
Analogs of any of the compounds listed in Tables Ia and Ib may be used in any of the methods, kits, and compositions described herein. Analogs are described herein.
Particularly effective therapeutic agents that may be used in the compositions, methods, and kits described herein include tricyclic antidepressants, ionophore antibiotics, cannabinoid agonists, channel blockers, antihistamines, SSRIs, anticholinergics, EKK- β inhibitors, and estrogen modulators, as described in more detail below.
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) generally work by inhibiting the re- uptake of neurotransmitters, such as norepinephrine, dopamine, or serotonin, by nerve cells. TCAs may be used to treat neurodegenerative disorders. TCAs that may be suitable for use in the compositions, kits, and methods described herein include, e.g., amoxapine, amitriptyline, BTCP hydrochloride, clomipramine (e.g., clomipramine hydrochloride), desipramine, dothiepin, doxepin, duloxetine, fluoxetine hydrochloride, fluvoxamine maleate, 7- hydroxyamoxapine, 8-hydroxyamoxapine, 8-hydroxyloxapine, imipramine, lofepramine, loxapine (e.g., loxapine succinate, loxapine hydrochloride), maprotiline hydrochloride, norfluoxetine, nortriptyline (e.g., nortriptyline hydrochloride), paroxetine hydrochloride, protriptyline, sertraline hydrochloride, and trimipramine.
Nortriptyline Nortriptyline has the structure:
Figure imgf000031_0001
Exemplary analogs of nortriptyline are amitriptylin, amoxapine, butriptyline, clomipramine, dothiepin, doxepin, desipramine, 8- hydroxyamoxapine, 7-hydroxyamoxapine, 8-hydroxyloxapine, imipramine, iprindole, lofepramine, loxapine, loxapine succinate, loxapine hydrochloride, maprotiline, mianserin, octriptyline, opipramol, oxaprotiline, protriptyline, trimipramine, and pharmaceutically acceptable salts thereof (described, e.g., in U.S. Patent Nos. 4,933,438 and 4,931,435), which are tricyclic antidepressants or act by blocking neuroepinephrine transport. Analogs of nortriptyline are also described by Formula PP in U.S. Application Publication No. 2005- 0080265.
Ionophore Antibiotics
Ionophores disrupt transmembrane ion concentration gradients, required for the proper functioning and survival of cells, and thus have antibiotic properties. Ionophore antibiotics may be used to treat neurodegenerative disorders. Ionophore antibiotics that may be suitable for use in the compositions, kits, and methods described herein include, e.g., alborixin, antibiotic A204, antibiotic X206, antibiotic A32887, antibiotic X-14766A, beauvericin, calcimycine (also referred to as A23187), calixarene, CCCP, chlorogenic acid, Compound 47,224, Compound 51,532, crown ether, dianemycin, dinactin, 2,4-dinitrophenol, NjN-dioctadecylmethylamine (also referred to as Proton ionophore III), etheromycin, FCCP, gramicidin A, grisorixin, ionomycin, isolasalocid A, K41, lasalocid (factors A, B, C, D, and E, individually or various combinations thereof), Ionomycin, laidlomycin, lenoremycin, lysocellin, maduramicin (e.g., maduramicin ammonium), monactin, monensin, mutalomycin, narasin, nigericin, nonactin (also referred to as ammonium ionophore I), 4-nonadecylpyridine (also referred to as proton ionophore II), salinomycin sodium, semduramicin, septamycin, tetranactin, tetronasin, trinactin, and valinomycin.
Maduramicin
Maduramicin has the following structure:
OCH3
Figure imgf000032_0001
Analogs of Maduramicin include the other polyether antiobiotics named above.
Cannabinoid Agonists Cannabinoid agonists include a group of substances that are structurally related to THC or that bind to cannabinoid receptors (e.g., diterpene C21 compounds present in Cannabis sativa L). Cannabinoid agonists may be used to treat neurodegenerative disorders. Cannabinoid agonists that may be suitable for use in the compositions, kits, and methods described herein include, e.g., ajulemic acid (IP-751), CP-55940, HU210, SR141716, SR144528, WIN 55,212-2, JWH-133, nabilone, levonantradol, marinol, sativex, tetrahydrocannabinol (THC), and analogs thereof.
WIN 55,212-2
WIN 55,212-2 has the following structure:
Figure imgf000033_0001
Analogs of WIN 55,212-2 include ligands and modulators of the CBl receptor and include: SR 141716A; Formulas (II) and (III) in U.S. Patent No. 6,825,209; Formulas (I) and (II) in U.S. Patent No. 5,596,106; and Formula (I) in U.S. Patent No. 6,509,367.
Channel Blockers Channel blockers are compounds, ranging from ions to complex organic molecules, that block the flow of ions through an ion channel. Channel blockers may be used to treat neurodegenerative disorders. Channel blockers that may be suitable for use in the compositions, kits, and methods described herein include, e.g., calcium channel blockers and sodium channel blockers. Calcium channel blockers include, e.g., dihydropyridines (e.g., amlodipine (e.g., amlodipine besylate); felodipine; lacidipine; lercanidipine; nicardipine; nifedipine; nimodipine; nisoldipine; and nitrendipine); phenylalkylamines (e.g., gallopamil and verapamil); benzodiazepines (e.g., diltiazem); and other agents, e.g., BAPTA-AM; bepridil; magnesium; and menthol; and paramethadione. Sodium channel blockers include, e.g., dibucaine (e.g., dibucaine hydrochloride); disopryamide; dyclonine (e.g., dyclonine hydrochloride); flecainide; lidocaine; mexiletine; moricizine; phenytoin; procainamide; propafenone; quinidine (e.g., quinidine gluconate); and tocainide. Additional channel blockers that may be useful include, e.g., levetiracetam.
Bepridil
Bepridil has the following structure:
Figure imgf000034_0001
Structural analogs of bepridil are described by Formula (I) and compounds (l)-(6) of U.S. Patent No. 3,962,238 and by Formula (I) in RE30,577.
Antihistamines Antihistamines are compounds that block the action of histamine.
Antihistamines may be used to treat neurodegenerative disorders. Classes of antihistamines include:
(1) Ethanolamines (e.g., bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, diphenylpyraline, and doxylamine);
(2) Ethylenediamines (e.g., pheniramine, pyrilamine, tripelennamine, and triprolidine);
(3) Phenothiazines (e.g., diethazine, ethopropazine, methdilazine (e.g., methdilazine hydrochloride), promethazine, thiethylperazine, and trimeprazine); (4) Alkylamines (e.g., acrivastine, brompheniramine, chlorpheniramine, desbrompheniramine, dexchlorpheniramine, pyrrobutamine, and triprolidine);
(5) Piperazines (e.g., buclizine, cetirizine, chlorcyclizine, cyclizine, meclizine, hydroxyzine); (6) Piperidines (e.g., astemizole, azatadine, cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen, olopatadine, phenindamine, and terfenadine);
(7) Atypical antihistamines (e.g., azelastine, levocabastine, methapyrilene, and phenyltoxamine). In the methods, compositions, and kits described herein, both nonsedating and sedating antihistamines may be employed. Exemplary antihistamines that may be used in the methods, compositions, and kits described herein are non-sedating antihistamines such as loratadine and desloratadine. Sedating antihistamines may also be used in the methods, compositions, and kits described herein. Exemplary sedating antihistamines of the methods, compositions, and kits described herein are azatadine, bromodiphenhydramine; chlorpheniramine; clemizole; cyproheptadine (e.g., cyproheptadine hydrochloride); dimenhydrinate; diphenhydramine; doxylamine; meclizine; promethazine (e.g., promethazine hydrochloride); pyrilamine; thiethylperazine; and tripelennamine.
Other antihistamines that may be suitable for use in the methods, compositions, and kits described herein are acrivastine; ahistan; antazoline (e.g., antazoline phosphate); astemizole; azelastine (e.g., azelsatine hydrochloride); bamipine; bepotastine; bietanautine; brompheniramine (e.g., brompheniramine maleate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; chloropyramine; chlorothen; chlorphenoxamine; cinnarizine; clemastine (e.g., clemastine fumarate); clobenzepam; clobenztropine; clocinizine; cyclizine (e.g., cyclizine hydrochloride; cyclizine lactate); deptropine; dexchlorpheniramine; dexchloφheniramine maleate; dimebon, diphenylpyraline; doxepin; ebastine; embramine; emedastine (e.g., emedastine difumarate); epinastine; etymemazine hydrochloride; fexofenadine (e.g., fexofenadine hydrochloride); flunarizine hydrochloride (e.g., flunarizine hydrochloride); histapyrrodine; homochlorcyclizine (e.g., homochlorcyclizine dihydrochloride); hydroxyzine (e.g., hydroxyzine hydrochloride; hydroxyzine pamoate); isopromethazine; isothipendyl; levocabastine (e.g., levocabastine hydrochloride); mebhydroline (e.g., mebhydroline 1,5-naphthalenedisulfonate salt); mequitazine; methafurylene; methapyrilene; methotrimeprazine; metron; mizolastine; olapatadine (e.g., olopatadine hydrochloride); orphenadrine; phenindamine (e.g., phenindamine tartrate); pheniramine; phenyltoloxamine (e.g., phenyltoloxamine citrate); pimethixene; p-methyldiphenhydramine; pyrrobutamine; setastine; talastine; terfenadine; thenyldiamine; thiazinamium (e.g., thiazinamium methylsulfate); thonzylamine hydrochloride; tolpropamine; triprolidine; and tritoqualine.
Structural analogs of antihistamines may also be used. Antihistamine analogs include, without limitation, 10-piperazinylpropylphenothiazine; 4-(3- (2-chlorophenothiazin- 10-yl)propyl)- 1 -piperazineethanol dihydrochloride; 1 - ( 10-(3 -(4-methy 1- 1 -piperaziny l)propy I)- 1 OH-phenothiazin-2-y 1)-(9CI) 1 - propanone; 3-methoxycyproheptadine; 4-(3-(2-Chloro-10H-phenothiazin-10- yl)propyl)piperazine-l-ethanol hydrochloride; 10,1 l-dihydro-5-(3-(4- ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H- dibenzo(a,d)cycloheptene; aceprometazine; acetophenazine; alimemazin (e.g., alimemazin hydrochloride); aminopromazine; benzimidazole; butaperazine; carfenazine; chlorfenethazine; chlormidazole; cinprazole; desmethylastemizole; desmethylcyproheptadine; diethazine (e.g., diethazine hydrochloride); ethopropazine (e.g., ethopropazine hydrochloride); 2-(p-bromophenyl-(p'- tolyl)methoxy)-N,N-dimethyl-ethylamine hydrochloride; N,N-dimethyl-2- (diphenylmethoxy)-ethylamine methylbromide; EX-10-542A; fenethazine; fuprazole; methyl 10-(3-(4-methyl- 1 -piperazinyl)propyl)phenothiazin-2-yl ketone; lerisetron; medrylamine; mesoridazine; methylpromazine; N- desmethylpromethazine; nilprazole; northioridazine; perphenazine (e.g., perphenazine enanthate); 10-(3-dimethylaminopropyl)-2-methylthio- phenothiazine; 4-(dibenzo(b,e)thiepin-6(l lH)-ylidene)-l-methyl-piperidine hydrochloride; prochloφerazine; promazine; propiomazine (e.g., propiomazine hydrochloride); rotoxamine; rupatadine; Sch 37370; Sch 434; tecastemizole; thiazinamium; thiopropazate; thioridazine (e.g., thioridazine hydrochloride); and 3-(10,l l-dihydro-5H-dibenzo(a,d)cyclohepten-5-ylidene)-tropane. Other antihistamine analogs that may be suitable are AD-0261 ; AHR-
5333; alinastine; arpromidine; ATI-19000; bermastine; bilastin; Bron-12; carebastine; chlorphenamine; clofurenadine; corsym; DF-1105501 ; DF-11062;
DF-1111301 ; EL-301; elbanizine; F-7946T; F-9505; HE-90481; HE-90512; hivenyl; HSR-609; icotidine; KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674; levocetirizine; levoprotiline; metoclopramide; NIP-531; noberastine; oxatomide; PR-881-884A; quisultazine; rocastine; selenotifen;
SK&F-94461 ; SODAS-HC; tagorizine; TAK-427; temelastine; UCB-34742;
UCB-35440; VUF-K-8707; Wy-49051; and ZCR-2060.
Still other antihistamine analogs that may be suitable are described in U.S. Patent Nos. 3,956,296; 4,254,129; 4,254,130; 4,282,833; 4,283,408;
4,362,736; 4,394,508; 4,285,957; 4,285,958; 4,440,933; 4,510,309; 4,550,116;
4,692,456; 4,742,175; 4,833,138; 4,908,372; 5,204,249; 5,375,693; 5,578,610;
5,581,011; 5,589,487; 5,663,412; 5,994,549; 6,201,124; and 6,458,958.
Clemastine
Clemastine has the following structure:
Figure imgf000038_0001
Structural analogs of Clemastine are described by Formula (I) of Great Britain Patent No. 942152 and by Formula (C) of U.S. Patent No. 7,355,042.
Exemplary clemastine analogs include: N-methy 1-2- [2 '-(p- chlorobenzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2' -benzyhy dry loxy)- ethyl]-piperidine; N-methyl-2-[2'-(p-bromo-benzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2 ' -(p-fluoro-benzhy dry loxy )-ethy 1] -piperidine; N-methy 1-2- [2 ' - (p-methyl-benzhydryloxy)-ethyl]-piperidine; N-methyl-2-[2'-(p- methoxyzbenzhydryloxy) ethyl]-piperidine; N-methy 1-2- [2'- ( -methyl- benzhydryloxy)-ethyl]-piperidine; N-methy 1-2- [2' -(α-methy 1-p-chloro- benzhydryloxy)-ethyl]-piperidine; N-methyl-2-[2'-(α-methyl-p-bromo- benzhydryloxy)-ethyl]-piperidine; N-methyl-2-[2'-(α-methyl-p-methyl- benzhydryloxy)-ethyl]-piperidine; N-methyl-2-[2'-(α-methyl-benzhydryloxy)- ethyl]-pyrrolidine; N-methyl-2-[2'-(α-methyl-p-chloro-benzhydryloxy)-ethyl]- pyrrolidine; N-methyl-2-[2'-(α-methyl-p-bromo-benzhydryloxy)-ethyl]- pyrrolidine; N-methyl-2-[2'-(α-p-methyl-benzhydryloxy)-ethyl]-pyrrolidine.
Cyproh eptadine
Cyproheptadine has the following structure:
Figure imgf000038_0002
Structural analogs of cyproheptadine are described in U.S. Patent No. 3,014,911. Structural analogs are also described by the following structure:
Figure imgf000039_0001
wherein, independently, R1, R2, R3, R4, K5, R6, R7, and Rg are each selected from H, C1-6 alkyl, perhalogenated C1-6 alkyl, OH, OCi-6 alkyl, OCF3, SH, SC1. 6 alkyl, or SCF3; Y is CH2, O, NH, S(O)0-2, (CH2)3, (CH)2, CH2O, CH2NH, CHN, or CH2S; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; R9 is H or Ci-6 alkyl; B1 and B2 are selected from H, perhalogenated C1-6 alkyl, Ci-6 alkyl, or B1 and B2, B1 and R9, or B2 and R9 join together to form an optionally substituted ring.
Selective Serotonin Reuptake Inhibitors
The methods, compositions, and kits described herein may employ an SSRI, or a structural or functional analog thereof. Suitable SSRIs may include amoxapine; BTCP (e.g., BTCP hydrochloride); cericlamine (e.g., cericlamine hydrochloride); citalopram (e.g., citalopram hydrobromide); clovoxamine; cyanodothiepin; dapoxetine; dothiepin; duloxetine; escitalopram (escitalopram oxalate); femoxetine (e.g., femoxetine hydrochloride); fenfluramine (e.g., fenfluramine hydrochloride); fluoxetine (e.g., fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride); indeloxazine (e.g., indeloxazine hydrochloride); litoxetine; metergoline; milnacipran (e.g., minlacipran hydrochloride); paroxetine (e.g., paroxetine hydrochloride hemihydrate; paroxetine maleate; paroxetine mesylate); protriptyline (e.g., protriptyline hydrochloride); sertraline (e.g., sertraline hydrochloride); tametraline hydrochloride; viqualine; and zimeldine (e.g., zimeldine hydrochloride).
Cericlamine Cericlamine has the following structure:
Figure imgf000040_0001
Structural analogs of cericlamine are those having the formula:
Figure imgf000040_0002
as well as pharmaceutically acceptable salts thereof, wherein R1 is a C1-C6 alkyl and R2 is H or Q-C6 alkyl, R3 is H, C1-C6 alkyl, C2-C6 alkenyl, phenylalkyl or cycloalkylalkyl with 3 to 6 cyclic carbon atoms, alkanoyl, phenylalkanoyl or cycloalkylcarbonyl having 3 to 6 cyclic carbon atoms, or R2 and R3 form, together with the nitrogen atom to which they are linked, a heterocycle saturated with 5 to 7 chain links which can have, as the second heteroatom not directly connected to the nitrogen atom, an oxygen, a sulphur or a nitrogen, the latter nitrogen heteroatom possibly carrying a C2-C6 alkyl.
Exemplary cericlamine structural analogs are 2-methyl-2-amino-3-(3,4- dichlorophenyl)-propanol, 2-pentyl-2-amino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2-methylamino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2- dimethylamino-3-(3,4-dichlorophenyl)-propanol, and pharmaceutically acceptable salts of any thereof. Citalopram
Citalopram has the following structure:
Figure imgf000041_0001
Structural analogs of citalopram are those having the formula:
Figure imgf000041_0002
as well as pharmaceutically acceptable salts thereof, wherein each Of R1 and R2 is independently selected from the group consisting of bromo, chloro, fluoro, trifluoromethyl, cyano and R-CO-, wherein R is C1-C6 alkyl.
Exemplary citalopram structural analogs (which are thus SSRI structural analogs) are l-(4'-fluorophenyl)-l-(3-dimethylaminopropyl)-5- bromophthalane; l-(4'-chlorophenyl)-l-(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-bromophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -(4'-bromophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethyl-phthalane; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- fluorophthalane; 1 -(4'-chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- fluorophthalane; 1 -(4'-chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- phthalancarbonitrile; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- phthalancarbonitrile; l-(4'-cyanophenyl)-l-(3-dimethylaminopropyl)-5- phthalancarbonitrile; 1 -(4'-cyanophenyl)- 1 -(3-dimethylaminopropyl)-5- chlorophthalane; 1 -(4'-cyanophenyl)- 1 -(3-dimethylaminopropyl)-5- trifluoromethylphthalane; 1 -(4'-fluorophenyl)- 1 -(3-dimethylaminopropyl)-5- phthalancarbonitrile; 1 -(4'-chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- ionylphthalane; 1 -(4-(chlorophenyl)- 1 -(3-dimethylaminopropyl)-5- propionylphthalane; and pharmaceutically acceptable salts of any thereof.
Clovoxamine
Clovoxamine has the following structure:
Figure imgf000042_0001
Structural analogs of clovoxamine are those having the formula:
Figure imgf000042_0002
as well as pharmaceutically acceptable salts thereof, wherein Hal is a chloro, bromo, or fluoro group and R is a cyano, methoxy, ethoxy, methoxy methyl, ethoxymethyl, methoxyethoxy, or cyanomethyl group. Exemplary clovoxamine structural analogs are 4'-chloro-5- ethoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-5-(2- methoxyethoxy)valerophenone O-(2-aminoethyl)oxime; 4'-chloro-6- methoxycaprophenone O-(2-aminoethyl)oxime; 4'-chloro-6- ethoxycaprophenone O-(2-aminoethyl)oxime; 4'-bromo-5-(2- methoxyethoxy)valerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- methoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro-6- cyanocaprophenone O-(2-aminoethyl)oxime; 4'-chloro-5-cyanovalerophenone O-(2-aminoethyl)oxime; 4'-bromo-5-cyanovalerophenone O-(2- aminoethyl)oxime; and pharmaceutically acceptable salts of any thereof.
Femoxetine
Femoxetine has the following structure:
Figure imgf000043_0001
Structural analogs of femoxetine are those having the formula:
Figure imgf000043_0002
wherein Ri represents a Ci-C6 alkyl or C2-C6 alkynyl group, or a phenyl group optionally substituted by C1-C6 alkyl, CpC6 alkylthio, CpC6 alkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy, or tetrahydronaphthyl, R2 represents a C1-C6 alkyl or C2-C6 alkynyl group, and R3 represents hydrogen, C1-C6 alkyl, C]-C6 alkoxy, trifluoroalkyl, hydroxy, bromo, chloro, fluoro, methylthio, or aralkyloxy.
Exemplary femoxetine structural analogs are disclosed in Examples 7- 67 of U.S. Patent No. 3,912,743.
Fluoxetine
Fluoxetine has the following structure:
Figure imgf000044_0001
Structural analogs of fluoxetine are those compounds having the formula:
Figure imgf000044_0002
as well as pharmaceutically acceptable salts thereof, wherein each R1 is independently hydrogen or methyl; R is naphthyl or
Figure imgf000044_0003
wherein each of R2 and R3 is, independently, bromo, chloro, fluoro, trifluoromethyl, Q-C6 alkyl, C1-C3 alkoxy or C3-C4 alkenyl; and each of n and m is, independently, 0, 1 or 2. When R is naphthyl, it can be either α-naphthyl or β-naphthyl. Exemplary fluoxetine structural analogs are 3-(p-isopropoxyphenoxy)-3- phenylpropylamine methanesulfonate, N,N-dimethyl 3-(3',4'- dimethoxyphenoxy)-3 -phenylpropy lamine p-hy droxybenzoate, N,N-dimethy 1 3-(α-naphthoxy)-3-phenylpropylamine bromide, N,N-dimethyl 3-(β- naphthoxy)-3-phenyl-l-methylpropy lamine iodide, 3-(2'-methyl-4',5l- dichlorophenoxy)-3 -phenylpropy lamine nitrate, 3-(p-t-butylphenoxy)-3- phenylpropylamine glutarate, N-methyl 3-(2'-chloro-p-tolyloxy)-3-phenyl-l- methylpropylamine lactate, 3-(2',4'-dichlorophenoxy)-3-phenyl-2- methylpropylamine citrate, N,N-dimethyl 3 -(m-anisyloxy)-3 -phenyl- 1- methylpropy lamine maleate, N-methyl 3 -(p-to Iy loxy)-3 -phenylpropy lamine sulfate, N,N-dimethyl 3 -(2',4'-difluorophenoxy)-3 -phenylpropy lamine 2,4- dinitrobenzoate, 3 -(o-ethylphenoxy)-3 -phenylpropy lamine dihydrogen phosphate, N-methyl 3-(2'-chloro-4'-isopropylphenoxy)-3-phenyl-2- methylpropy lamine maleate, N,N-dimethyl 3-(2'-alkyl-4'-fluorophenoxy)-3- phenyl-propylamine succinate, N,N-dimethyl 3-(o-isopropoxyphenoxy)-3- phenyl-propy lamine phenylacetate, N,N-dimethyl 3-(o-bromophenoxy)-3- phenyl-propylamine β-phenylpropionate, N-methyl 3-(p-iodophenoxy)-3- phenyl-propy lamine propiolate, and N-methyl 3-(3-n-propylphenoxy)-3- phenyl-propylamine decanoate.
Fluvoxamine
Fluvoxamine has the following structure:
Figure imgf000045_0001
Structural analogs of fluvoxamine are described by Formula (I) in U.S. Patent No. 4,085,225. Structural analogs of fluvoxamine are also described by the formula:
Figure imgf000046_0001
as well as pharmaceutically acceptable salts thereof, wherein R is cyano, cyanomethyl, methoxymethyl, or ethoxymethyl.
Indalpine
Indalpine has the following structure:
Figure imgf000046_0002
Structural analogs of indalpine are those having the formula:
Figure imgf000046_0003
or pharmaceutically acceptable salts thereof, wherein R1 is a hydrogen atom, a CpC6 alkyl group, or an aralkyl group of which the alkyl has 1 or 2 carbon atoms, R2 is hydrogen, Q-C6 alkyl, CpC6 alkoxy or CpC6 alkylthio, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy, or amino, the latter optionally substituted by one or two Cj-C6 alkyl groups, an acyl group or a C1-C6 alkylsulfonyl group; A represents -CO or -CH2- group; and n is 0, 1 or 2. Exemplary indalpine structural analogs are indolyl-3 (piperidyl-4 methyl) ketone; (methoxy-5-indolyl-3) (piperidyl-4 methyl) ketone; (chloro-5- indolyl-3) (piperidyl-4 methyl) ketone; (indolyl-3 )-l(piperidyl-4)-3 propanone, indolyl-3 piperidyl-4 ketone; (methyl- 1 indolyl-3) (piperidyl-4 methyl) ketone, (benzyl- 1 indolyl-3) (piperidyl-4 methyl) ketone; [(methoxy-5 indolyl-3)-2 ethyl]-piperidine, [(methyl- 1 indolyl-3)-2 ethyl] -4-piperi dine; [(indolyl-3 )-2 ethyl]-4 piperidine; (indolyl-3 methyl)-4 piperidine, [(chloro-5 indolyl-3)-2 ethyl]-4 piperidine; [(indolyl-b 3)-3 propyl]-4 piperidine; [(benzyl- 1 indolyl-3)- 2 ethyl]-4 piperidine; and pharmaceutically acceptable salts of any thereof.
Indeloxazine
Indeloxezine has the following structure:
Figure imgf000047_0001
Structural analogs of indeloxazine are those having the formula:
Figure imgf000047_0002
and pharmaceutically acceptable salts thereof, wherein R1 and R3 each represents hydrogen, C1-C^ alkyl, or phenyl; R2 represents hydrogen, C1-C6 alkyl, C4-C7 cycloalkyl, phenyl, or benzyl; one of the dotted lines means a single bond and the other means a double bond, or the tautomeric mixtures thereof. Exemplary indeloxazine structural analogs are 2-(7-indenyloxymethyl)- 4-isopropylmoφholine; 4-butyl-2-(7-indenyloxymethyl)morpholine; 2-(7- indenyloxymethyl)-4-methylmorpholine; 4-ethyl-2-(7- indenyloxymethyl)moφholine, 2-(7-indenyloxymethyl)-morpholine; 2-(7- indenyloxymethyl)-4-propylmoφholine; 4-cyclohexyl-2-(7- indenyloxymethyl)moφholine; 4-benzyl-2-(7-indenyloxymethyl)-moφholine; 2-(7-indenyloxymethyl)-4-phenylmoφholine; 2-(4- indenyloxymethyl)moφholine; 2-(3-methyl-7-indenyloxymethyl)-moφholine; 4-isopropyl-2-(3-methyl-7-indenyloxymethyl)moφholine; 4-isopropyl-2-(3- methyl-4-indenyloxymethyl)moφholine; 4-isopropyl-2-(3-methyl-5- indenyloxymethyl)moφholine; 4-isopropyl-2-(l-methyl-3-phenyl-6- indenyloxymethyl)moφholine; 2-(5-indenyloxymethyl)-4-isopropyl- moφholine, 2-(6-indenyloxymethyl)-4-isopropylmoφholine; and 4-isopropyl- 2-(3-phenyl-6-indenyloxymethyl)moφholine; as well as pharmaceutically acceptable salts of any thereof.
Milnacipram
Milnacipram has the following structure:
Figure imgf000048_0001
Structural analogs of milnacipram are those having the formula:
Figure imgf000049_0001
as well as pharmaceutically acceptable salts thereof, wherein each R, independently, represents hydrogen, bromo, chloro, fluoro, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, nitro or amino; each of Rj and R2, independently, represents hydrogen, Q-C6 alkyl, C6-Ci2 aryl or C7-C14 alkylaryl, optionally substituted, for example, in para position, by bromo, chloro, or fluoro, or Rj and R2 together form a heterocycle having 5 or 6 members with the adjacent nitrogen atoms; R3 and R4 represent hydrogen or a CpC6 alkyl group or R3 and R4 form with the adjacent nitrogen atom a heterocycle having 5 or 6 members, optionally containing an additional heteroatom selected from nitrogen, sulphur, and oxygen.
Exemplary milnacipram structural analogs are 1 -phenyl 1- aminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- ethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1 -phenyl 1- diethylaminocarbonyl 2-aminomethyl cyclopropane; 1 -phenyl 2- dimethylaminomethyl N-(4'-chlorophenyl)cyclopropane carboxamide; 1- phenyl 2-dimethylaminomethyl N-(4'-chlorobenzyl)cyclopropane carboxamide; 1 -phenyl 2-dimethylaminomethyl N-(2-phenylethyl)cyclopropane carboxamide; (3,4-dichloro-l -phenyl) 2-dimethylaminomethyl N5N- dimethylcyclopropane carboxamide; 1 -phenyl 1-pyrrolidinocarbonyl 2- morpholinomethyl cyclopropane; 1-p-chlorophenyl 1-aminocarbonyl 2- aminomethyl cyclopropane; 1-orthochlorophenyl 1-aminocarbonyl 2- dimethylaminomethyl cyclopropane; 1-p-hydroxyphenyl 1-aminocarbonyl 2- dimethylaminomethyl cyclopropane; 1-p-nitrophenyl 1-dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-p-aminophenyl 1- dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-p-tolyl 1- methylaminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-p- methoxyphenyl 1-aminomethylcarbonyl 2-aminomethyl cyclopropane; and pharmaceutically acceptable salts of any thereof.
Paroxetine Paroxetine has the following structure:
Figure imgf000050_0001
Structural analogs of paroxetine are those having the formula:
Figure imgf000050_0002
and pharmaceutically acceptable salts thereof, wherein Rj represents hydrogen, optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; R2 is optionally substituted Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-C6-heterocyclyl or C6-Ci2 aryl; X is any halogen and may be in any of the available positions; and Y is O or S. Paroxetine analogs may be used as stereochemical mixtures or in stereochemically pure form. An exemplary value for R2 is optionally substituted 1,3-benzodioxole. Analogs of paroxetine are described in Formula (I) and Examples 7-67 of U.S. Patent No. 3,912, 743; Formula (I) of U.S. Patent No. 4,985,446; Formula (I) of U.S Patent No. 5,158,961; Formula (I) of U.S. Patent No. 6,900,327. Exemplary paroxetine analogs are:
(-)-trans-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-l- ethylpiperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4- methylenedioxyphenoxymethyl)- 1 -propylpiperidine; (-)-trans-4-(-4- fluoropheny l)-3 -(3 ,4-methy lenedioxyphenoxymethyl)- 1 -buty lpiperidine hydrochloride; (-)-trans-4-(-4-fluorophenyl)-3 -(3 ,4- methy lenedioxyphenoxymethyl)- 1 -octy lpiperidine; (-)-trans-4-(-4- fluorophenyl)-3 -(3 ,4-methylenedioxyphenoxymethyl)- 1 -isopentylpiperidine; (- )-trans-4-(-4-fluorophenyl)-3-(3 ,4-methylenedioxyphenoxymethyl)- 1-(4- phenoxybutyl)piperidine;
(-)-trans-4-(-4-fluorophenyl)-3 -(3 ,4-methylenedioxyphenoxymethyl)- 1 - hexylpiperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4- methy lenedioxyphenoxymethyl)- 1 -(3-phenylpropyl)piperidine; (-)-trans-4-(-4- fluorophenyl)-3 -(3, 4-methy lenedioxyphenoxymethyl)- 1 -(2-ethy lhexyl)- piperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3 ,4- methy lenedioxyphenoxymethyl)- 1 -(3 ,3 -di methylbutyl)-piperidine; (-)-trans-4- (-4-fluorophenyl)-3 -(3 ,4-methylenedioxyphenoxymethyl)- 1 -cyclohexyl- piperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4- methylenedioxyphenoxymethyl)-l-heptyl- piperidine hydrochloride; (-)-trans- 4-(-4-fluoropheny l)-3 -(3 ,4-methylenedioxyphenoxymethyl)- 1 -cyclopenty 1- piperidine; (-)-trans-4-(-4-fluorophenyl)-3 -(3 ,4- methylenedioxyphenoxymethyl)- 1 -allyl-piperidine; (-)-trans-4-(-4- fluorophenyl)-3 -(3, 4-methy lenedioxyphenoxymethyl)- 1 - cyclopropylmethylpiperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4- methylenedioxyphenoxymethyl)- 1 -cycloheptyl-piperidine; (-)-trans-4-(-4- fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-l-(2-ethoxyethyl)- piperidine; (-)-trans-4-(-4-fluorophenyl)-3 -(3 ,4- methylenedioxyphenoxymethyl)- 1 -(2-methoxymethyl)-piperidine; (-)-trans-4- (-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-l-(2-trans-butenyl)- piperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4- methylenedioxyphenoxymethyl)- 1 -(3-butenyl)-piperidine; (-)-trans-4-(-4- fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-l-(5-hexenyl)- piperidine; (-)-trans-4-(-4-fluorophenyl)-3-(3,4- methylenedioxyphenoxymethyl)-l-(4-pentenyl)-piperidine ; (-)-trans-4-(-4- fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-l-(3-methyl-butenyl)- piperidine; (-)-cis-4-(-4-fluorophenyl)-3-(3,4-methylenedioxyphenoxyme-thyl)- 1-pentylpiperidine; (-)-trans-l-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxy- methyl)-piperidine; (-)-trans-l-propyl-4-(4-fluorophenyl)-3-(4- methoxyphenoxy-methyl)-piperidine hydrochloride; (-)-trans-l-ethyl-4-(4- fluoropheny l)-3 -(4-methoxyphenoxy-methy l)-piperidine; (-)-trans- 1 -isopropyl- 4-(4-fluorophenyl)-3-(4-methoxyphenoxy-methyl)-piperidine; (-)-trans- 1 -(2- (4-methoxyphenoxyethyl))-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)- piperidine; (-)-trans- 1 -pentyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxy- methyl)-piperidine; (-)-trans-l-heptyl-4-(4-fluorophenyl)-3-(4- methoxyphenoxy-methy l)-piperidine; (-)-trans- 1 -cyclohexyl-4-(4- fluorophenyl)-3-(4-methoxy-phenoxymethyl)-piperidine; trans- 1 -propyl-4-(4- fluorophenyl)-3-(4-t-butylphenoxy-methyl)-piperidine; trans- 1 -ethyl-4-(4- fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine; trans- 1 -butyl-4-(4- fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine; (-)trans 3-(2- Cyclohexylphenoxymethyl)-4-(4-fluorophenyl)- 1 -methyl-piperidine trans 4-(4-Fluorophenyl)- 1 -methyl-3-(5,6,7,8,-tetrahydro2-naphthoxymethyl)- piperidine; trans 3-(4-Benzyloxyphenoxymethyl)-4-(4-fluorophenyl)-l- methylpiperidine; trans 3-(4-Benzyloxy-3-methoxyphenoxymethyl)-4-(4- fluorophenyl)- 1-methylpiperidine; trans 4-(4-Fluorophenyl)-l-methyl-3-(2- naphthoxymethyl)-piperidine; trans 3-(2-Cyclohexylphenoxymethyl)-4-(4- fluorophenyl)-piperidine; trans 3-(4-Benzyloxyphenoxymethyl)-4- phenylpiperidine; trans 4-(4-Fluorophenyl)-3-(5,6,7,8,-tetrahydro-2- naphthoxymethyl)-piperidine; trans 3-(4-Benzyloxyphenoxymethyl)-4-(4- fluorophenyl)-piperidine; (-)-trans 3-(2-Benzothiazolylthiomethyl)-4-(4- fluorophenyl)-piperidine; (-)-trans 4-(4-Fluorophenyl)-3-(2-naphthoxymethyl)- piperidine; (-) trans 3-(2-Cyclohexylphenoxymethyl)-4-(4-fluorophenyl)-l- pentylpiperidine; (+/-) trans 3-(4-Benzyloxyphenoxymethyl)-l-pentyl-4- phenylpiperidine; (+/-) trans 1- Ally 1-3 -(4-benzyloxyphenoxymethyl)-4- phenylpiperidine; (-) trans 3-(4-Methoxyphenoxymethyl)-l-pentyl-4- phenylpiperidine; (-) trans l-Allyl-3-(4-methoxyphenoxymethyl)-4- phenylpiperidine; (+) trans 3-(4-Methoxyphenoxymethyl)-l-pentyl-4- phenylpiperidine; (+) trans l-Allyl-3-(4-methoxyphenoxymethyl)-4- phenylpiperidine; (-) trans 4-(4-Fluorophenyl)-l-pentyl-3-(5,6,7,8-tetrahydro- 2-naphthoxymethyl)-piperidine; (-) trans 3-(2-Benzothiazolylthiomethyl)-4-(4- fluorophenyl)-l-pentylpiperidine; (-) trans 4-(-Fluorophenyl)-3-(2- naphthoxymethyl)-l-pentylpiperidine; (-) trans l-Butyl-4-(4-fluorophenyl)-3- (5,6,7,8-tetrahydro-2-naphthoxymethyl)-piperidine; (-) trans 4-(4- Fluorophenyl)- l-propyl-3-(5,6,7,8-tetrahydro-2-naphthoxymethyl)-piperidine; (-) trans 4-(4-Fluorophenyl)-l-hexyl-3-(5,6,7,8-tetrahydro-2- naphthoxymethyl)-piperidine; (-) trans l-Ethyl-4-(4-Fluorophenyl)-3-(5,6,7,8- tetrahydro-2-naphthoxymethyl)-piperidine; and (-) trans 3-(2- Benzothiazolylthiomethyl)-4-(4-fluorophenyl)- 1 -methylpiperidine.
Sertraline
Sertraline has the following structure:
Figure imgf000053_0001
Structural analogs of sertraline are those having the formula:
Figure imgf000054_0001
wherein, independently, R1, R2, R3, R4, R5, and R6 is hydrogen or optionally substituted C1-G6 alkyl; X and Y are each selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, C1-C3 alkoxy, and cyano; and W is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and C1-C3 alkoxy. In some embodiments, the sertraline analogs are in the cis-isomeric configuration. The term "cis-isomeric" refers to the relative orientation of the NRiR2 and phenyl moieties on the cyclohexene ring (i.e. they are both oriented on the same side of the ring). Because both the 1- and 4- carbons are asymmetrically substituted, each cis- compound has two optically active enantiomeric forms denoted (with reference to the 1 -carbon) as the cis-(lR) and cis-(l S) enantiomers.
Certain useful are the following compounds, in either the (IS)- enantiomeric or (IS)(IR) racemic forms, and their pharmaceutically acceptable salts: cis-N-methyl-4-(3,4-dichlorophenyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenamine; cis-N-methyl-4-(4-bromophenyl)- 1 ,2,3,4-tetrahydro- 1 - naphthalenamine; cis-N-methyl-4-(4-chloropheny I)- 1,2,3, 4-tetrahydro-l - naphthalenamine; cis-N-methyl-4-(3-trifluoromethyl-phenyl)- 1 ,2,3,4- tetrahydro- 1 -naphthalenamine; cis-N-methy l-4-(3 -trifluoromethyl-4- chloropheny I)- 1,2,3, 4-tetrahydro-l -naphthalenamine; cis-N,N-dimethyl-4-(4- chloropheny I)-1, 2,3, 4-tetrahydro-l -naphthalenamine; cis-N,N-dimethyl-4-(3- trifluoromethyl-phenyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenamine; and cis-N- methy l-4-(4-chlorophenyl)-7-chloro- 1,2, 3, 4-tetrahydro-l -naphthalenamine. Of interest also is the (lR)-enantiomer of cis-N-methyl-4-(3,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenamine.
Sertraline analogs are also described in U.S. Pat. No. 4,536,518. Other related compounds include (S,S)-N-desmethylsertraline, rac-cis-N- desmethylsertraline, (lS,4S)-desmethyl sertraline, 1-des (methylamine)-l-oxo- 2-(R,S)-hydroxy sertraline, (lR,4R)-desmethyl sertraline, sertraline sulfonamide, sertraline (reverse) methanesulfonamide, 1R,4R sertraline enantiomer, N,N-dimethyl sertraline, nitro sertraline, sertraline aniline, sertraline iodide, sertraline sulfonamide NH2, sertraline sulfonamide ethanol, sertraline nitrile, sertraline-CME, dimethyl sertraline reverse sulfonamide, sertraline reverse sulfonamide (CH2 linker), sertraline B-ring ortho methoxy, sertraline A-ring methyl ester, sertraline A-ring ethanol, sertraline N5N- dimethylsulfonamide, sertraline A ring carboxylic acid, sertraline B-ring para- phenoxy, sertraline B-ring para-trifluoromethane, N,N-dimethyl sertraline B- Ring para-trifluoromethane, and UK-416244. Structures of these analogs are shown below.
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
raline
Figure imgf000060_0001
Figure imgf000061_0001
Zimeldine
Zimeldine has the following structure:
Figure imgf000061_0002
Structural analogs of zimeldine are those compounds having the formula:
Figure imgf000061_0003
and pharmaceutically acceptable salts thereof, wherein the pyridine nucleus is bound in ortho-, meta- or para-position to the adjacent carbon atom and where R1 is selected from the group consisting of H, chloro, fluoro, and bromo.
Exemplary zimeldine analogs are (e)- and (z)- 3-(4'-bromophenyl-3-(2"- pyridyl)-dimethylallylamine; 3-(4'-bromophenyl)-3-(3 "-pyridyl)- dimethylallylamine; 3-(4'-bromophenyl)-3-(4"-pyridyl)-dimethylallylamine; and pharmaceutically acceptable salts of any thereof.
Structural analogs of any of the above SSRIs are considered herein to be SSRI analogs and thus may be employed in any of the methods, compositions, and kits described herein.
Metabolites
Pharmacologically active metabolites of any of the foregoing SSRIs can also be used in the methods, compositions, and kits described herein. Exemplary metabolites are didesmethylcitalopram, desmethylcitalopram, desmethylsertraline, and norfluoxetine.
Analogs
Functional analogs of SSRIs can also be used in the methods, compositions, and kits described herein. Exemplary SSRI functional analogs are provided below. One class of SSRI analogs are SNRIs (selective serotonin norepinephrine reuptake inhibitors), which include venlafaxine and duloxetine.
Venlafaxine Venlafaxine has the following structure:
Figure imgf000063_0001
Structural analogs of venlafaxine are those compounds having the formula:
Figure imgf000063_0002
as well as pharmaceutically acceptable salts thereof, wherein A is a moiety of the formula:
Figure imgf000063_0003
where the dotted line represents optional unsaturation; R1 is hydrogen or alkyl; R2 is C]-C6 alkyl; R4 is hydrogen, CpC6 alkyl, formyl or alkanoyl; R3 is hydrogen or CpC6 alkyl; R5 and R6 are, independently, hydrogen, hydroxyl, CrC6 alkyl, CpC6 alkoxy, CpC6 alkanoyloxy, cyano, nitro, alkylmercapto, amino, C1-C6 alkylamino, dialkylamino, CpC6 alkanamido, halo, trifluoromethyl or, taken together, methylenedioxy; and n is 0, 1, 2, 3 or 4. Duloxetine
Duloxetine has the following structure:
Figure imgf000064_0001
Structural analogs of duloxetine are those compounds described by the formula disclosed in U.S. Patent No. 4,956,388 and in U.S. Patent No. 5,023,269 (see, for example, the formula at Col. 1, line 35 and the formula recited in Claim 1). Exemplary duloxetine analogs are: N-Methyl-3-(l-naphthalenyloxy)-3-(3- thienyl)-propanamine; N-Methyl-3-(2-naphthalenyloxy)-3-(cyclohexyl)- propanamine; N,N-Dimethyl-3-(4-chloro- 1 -naphthalenyloxy)-3-(3- furanyl)propanamine; N-Methyl-3-(5-methyl-2-naphthalenyloxy)-3-(2- thiazolyl)propanamine; N-Methyl-3-[3-(trifluoromethyl)- 1 -naphthalemyloxy]- 3-(3-methyl-2-thienyl)propanamine; N-Methyl-3-(6-iodo-l-naphthalenyloxy)- 3-(4-pyridyl)propanamine; N,N-Dimethyl-3-(l-naphthalenyloxy)-3- (cycloheptyl)propanamine; N,N-Dimethyl-3-(2-naphthalenyloxy)-3-(2- pyridyl)propanamine; N-Methyl-3-(l-naphthalenyloxy)-3-(2- furanyl)propanamine; N-Methyl-3-(4-met naphthalenyloxy)-3-(4- thiazolyl)propanamine; N-Methyl-3-(2-naphthalenyloxy)-3-(2- thienyl)propanamine; N,N-Dimethyl-3-6-iodo-2-naphthalenyloxy)-3-(4-bromo- 3-thienyl)propanamine; N,N-Dimethyl-3-( l-naphthalenyloxy)-3-(3- pyridyl)propanamine; N,N-Dimethyl-3-(4-methyl-2-naphthalenyloxy)-3-(3- furanyl)propanamine; N-Methyl-3-(2-naphthalenyloxy)-3- (cyclohexyl)propanamine; N-Methyl-3-(6-n-propyl-l-naphthalenyloxy)-3-(3- isopropyl-2-thienyl)propanamine; N,N-Dimethyl-3-(2-methyl- 1 - naphthalenyloxy)-3-(4-thiazolyl)propanamine; 3-( 1 -Naphthalenyloxy)-3-(5- ethyl-3-thienyl)propanamine; 3-3-(Trifluoromethyl)-l-naphthalenyloxy]-3- (pyridyl)propanamine; N-Methyl-3-(6-methyl- 1 -naphthalenyl-3-(4-chloro-2- thienyl)propanamine; 3-(2-Naphthalenyloxy)-3-(cyclopentyl)propanamine; N-Methyl-3-(4-n-butyl-l-naphthalenyloxy)-3-(3-furanyl)propanamine; 3-(2- Chloro- 1 -naphthaleny loxy )-3 -(5 -thiazoly l)propanamine; N-Methy 1-3 -( 1 - naphthalenyloxy)-3-(3-furanyl)propanamine; N,N-Dimethyl-3-(phenoxy)-3-(2- furany l)propanamine; N,N-Dimethy 1-3 - [4-(trifluoromethy l)phenoxy] -3 - (cyclohexyl)propanamine; N-Methyl-3-(4-methylphenoxy)-3-(4-chloro-2- thienyl)propanamine; N-Methyl-3-(phenoxy)-3-(3-pyridyl)propanamine; 3-[2- Chloro-4-(trifluoromethyl)phenoxy]-3-(2-thienyl)propanamine; N,N-Dimethyl- 3 -(3 -methoxyphenoxy )-3 -(3 -bromo-2-thieny l)propanamine; N-Methy 1-3 -(4- bromophenoxy)-3-(4-thiazolyl)propanamine; N,N-Dimethyl-3-(2- ethylphenoxy)-3-(5-methyl-3thienyl)propanamine; N-Methy 1-3 -(2- bromophenoxy)-3-(3-thienyl)propanamine; N-Methyl-3-(2,6- dimethy lphenoxy)-3 -(3 -methy 1-2-thieny l)propanamine; 3 - [3 - (Trifluoromethyl)phenoxy]-3-(3-furanyl)propanamine; N-Methyl-3-(2,5- dichlorophenoxy)-3-(cyclopentyl)propanamine; 3-4- (Trifluoromethyl)phenoxy]-3-(2-thiazolyl)propanamine; N-Methyl-3- (phenoxy)-3 -(5 -methy 1-2-thieny l)propanamine; 3-(4-Methylphenoxy)-3-(4- pyridyl)propanamine; N,N-Dimethyl-3-(3-methyl-5-bromophenoxy)-3-(3-. thienyl)propanamine; N-Methyl-3-(3-n-propylphenoxy)-3-(2- thienyl)propanamine; N-Methyl-3-(phenoxy)-3-(3-thienyl)propanamine; N- Methyl-3-(4-methoxyphenoxy)-3-(cycloheptyl) propanamine; 3-(2- Chlorophenoxy)-3-(5-thiazolyl)propanamine; 3-2-Chloro-4- (trifluoromethyl)phenoxy]-3-(3-thienyl)propanamine; 3-(Phenoxy)-3-(4- methyl-2-thienyl)propanamine; N,N-Dimethyl-3-(4-ethylphenoxy)-3-(3- pyridyl)propanamine; and N,N-Dimethyl-3-[4-(trifluoromethyl)phenoxy]-3-(2- pyridyl)propanamine.
Other SSRJ analogs are l,2,3,4-tetrahydro-N-methyl-4-phenyl-l- naphthy lamine hydrochloride; 1 ,2,3 ,4-tetrahydro-N-methyl-4-pheny 1-(E)- 1 - naphthylamine hydrochloride; N,N-dimethyl- 1 -phenyl- 1 -phthalanpropylamine hydrochloride; gamma-(4-(trifluoromethyl)phenoxy)-benzenepropanamine hydrochloride; BP 554; CP 53261; O-desmethylvenlafaxine; WY 45,818; WY 45,881; N-(3-fluoropropyl)paroxetine; and Lu 19005.
Anticholinergics
Anticholinergic agents are compounds that reduce the effects mediated by acetylcholine at a receptor site, e.g., in the central nervous system or peripheral nervous system. Anticholinergics include reversible competitive inhibitors of acetylcholine receptors, and are classified according to the receptors that are affected: antimuscarinic agents operate on the muscarinic acetylcholine receptors, and antinicotinic agents operate on the nicotinic acetylcholine receptors. Anticholinergic agents may be used to treat neurodegenerative disorders. Anticholinergic agents that may be suitable for use in the compositions, kits, and methods described herein include, e.g., atracurium; atropine; benztropine (e.g., benztropine mesylate); darifenacin; dicyclomine (e.g., dicyclomine hydrochloride); dimenhydrinate; diphenhydramine; doxacurium; ethopropazine (e.g., ethopropazine hydrochloride); flavoxate; ipratropium; mivacurium; oxybutynin; pancuronium; pirenzepine; scopolamine; solifenacin; suxamethonium (e.g., suxamethonium chloride); tiotropium; tolterodine (e.g., tolterodine tartrate); trihexyphenidyl (e.g., trihexyphenidyl hydrochloride); trimethaphan; tropicamide; tubocurarine; and vecuronium.
Benztropine
Benztropine has the following structure:
Figure imgf000067_0001
Structural analogs of benztropine are described by: Formula (I) in U.S. Patent No. 5,792,775; Formula (I) in WO2007/025005; and in U.S. Patent No. 5,506,359.
Eth opropazine
Ethopropazine has the structure
Figure imgf000067_0002
Structural analogs of ethopropazine are described in U.S. Patent No.
2,607,773. Analogs of ethopropazine can also be described by the formula:
Figure imgf000067_0003
wherein, independently, each Xj and X2 is selected from H, halogen, OH, CN, NO2, C1-6 alkyl, or OCi-6 alkyl; n is 0, 1, 2, 3, 4, 5, or 6; and R1, R2, and R3 are H or optionally substituted Ci-6 alkyl, or R2, and R3 join to form a ring.
Trihexyphenidyl hydrochloride
Trihexyphenidyl hydrochloride has the following structure:
Figure imgf000068_0001
Structural analogs of trihexyphenidyl are described by Formulas (I) and (II) in U.S. Patent No. 2,682,543 and by the general formula found in U.S. Patent No. 2,716,121. Structural analogs of trihexyphenidyl can also have the following structure
Figure imgf000068_0002
wherein, independently, Ri, R2, R3, R4, and R5 are H, halogen, OH, CN, NO2, C1-6 alkyl, or OCi-6 alkyl; Ai and A2 are H or optionally substituted Ci-6 alkyl, or A1 and A2 join together to form a ring; n is 1, 2, 3, 4, 5, or 6; and B1 and B2 are H or optionally substituted C1-6 alkyl, or B] and B2 join together to form a ring.
Estrogen Modulators
Estrogen modulators may be useful in the compositions, methods, and kits described herein. Estrogen modulators include selective and non-selective estrogen receptor modulators, and further include estrogen-like compounds that modulate estrogen levels. Estrogen modulators include estrogenic antagonists, e.g., antiestrogens, and estrogenic agonists. Selective estrogen receptor modulators are high affinity ligands for estrogen receptors but can serve as either agonists or antagonists, depending on the tissue in which they act.
Exemplary estrogen modulators are acolbifene, afimoxifene, arzoxifene, bazedoxifene, clomifene (or clomiphene), N-desmethyltamoxifen, desmethylated arzoxifene, droloxifene, faslodex, 4'-fluoro- desmethylatedarzoxifene, fispemifene, fiilvestrant, 4-hydroxy tamoxifen, idoxifene, lasofoxifene, levormeloxifene, miproxifene, nafoxidine, ormeloxifene, ospemifene, pipendoxifene, raloxifene, tamoxifen, toremifene, trioxifene, CI-680, CI-628, CN-55,956-27, MER-25, U-11,555A, U-I l5IOOA, ICI-46,669, ICI-46,474, diphenolhydrochrysene, erythro-MEA, Parke Davis CN-35,945, GW5638, EM-800, SP-500263, SR16234, ZK191703, MDL 103,323, LY-117018, LY353381, NNC 45-0781, allenolic acid, cyclofenil, ethamoxytriphetol, and triparanol and those compounds described in U.S. Pat. Nos. 7,151,196; 7,138,426,7,045,540; 7,196,119; 6,927,224; 6,906,086; 6,906,202; 6,894,064; 6,869,969; 6,875,775; 6,797,719; 6,750,213; 6,458,811 ; 6,132,774; 5,962,475; 5,384,332, 4,894,373; 4,536,516; 4,418,068; and 2,914,563.
Clomiphene Clomiphene has the following structure:
Figure imgf000069_0001
Structural analogs of clomiphene include the other olefinic diastereomer of clomiphene. Structural analogs are also described by the general formula in U.S. Patent No. 2,914,563; the general formula of U.S. Patent No. 5,410,080; and in U.S. Patent No. 5,189,212.
Raloxifene
Raloxifene has the following structure:
Figure imgf000070_0001
Exemplary structural analogs of raloxifene are LYl 17018 and LY317783. Analogs of raloxifene are also described by Formula (I) of U.S. Patent No. 5,610,167 and also in U.S. Patent Nos. 5,393,763; 5,457,117; 5,478,847; 5,811,120; 5,972,383; 6,458,811 ; 6,797,719; 6,894,064; 6,906,086; RE38,968; RE39,049; RE39,050; and RE39,708; and in WO2000037065.
Tamoxifen
Tamoxifen has the following structure:
Figure imgf000070_0002
Structural analogs of tamoxifen have the following structure:
Figure imgf000070_0003
wherein, independently, each Rla, Rlb, Rlc, Rld, R2a, R2b, R20 R2d, R2e, R3a, R3t» R3C, R3d5 and R3e is selected from H, halogen, C^6 alkyl, OH, or OCi-6 alkyl; R4, R5, and R6 are selected from H or optionally substituted Ci-6 alkyl; and n is 1, 2, 3, 4, 5, or 6. Analogs of tamoxifen are also described by: Formula (I) of U.S. Patent
No. 4,536,516; Formula (I) of U.S. Patent No. 4,806,685; Formula (I) of U.S. Patent No. 5,047,431; Formula (I) of U.S. Patent No. 5,807,899; Formula (I) and compounds (l)-(46) in Table 1 of U.S. Patent No. 6,875,775.
Exemplary analogs of tamoxifen also include: 4-hydroxy tamoxifen; N- desmethyltamoxifen; threo- l-[4-(2,3-epoxypropoxy)-phenyl]- 1 ,2-diphenyl- 3,3,3-trifluoro-propane; (E)l-[4-(2,3-epoxypropoxy)-phenyl]-l,2-diphenyl- 3,3,3-trifluoro-propene; (E)-l,2-diphenyl-3,3,3-trifluoro-l-[4-(2-[bis-(2- hydroxyethyl)-amino]-eth oxy)-phenyl)]-propene: (E)-l,2-diphenyl-3,3,3- trifluoro- 1 -[4-(2-[4-methylpiperazino]-ethoxy)-phenyl]-propene; 1 -[4-(2- dimethy laminoethoxy)-pheny l]-2-phenyl-3 ,3 ,3 -trifluoro- 1 -(4-methox yphenyl)- propene; l-[4-(2-dimethylaminoethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-l-(4- hydrox yphenyl)-propene; (E)-l,2-diphenyl-3,3,3-trifluoro-l-[4-(2-[2- hydroxyethylamino]-ethoxy)-ph enyl]-propene; 1 -[4-(2-dimethylaminoethoxy)- phenyl]- 1 -phenyl-3,3,3-trifluoro-2-(4-hydrox yphenyl)-propene; (E)- 1 ,2- diphenyl-3,3,3-trifluoro-2-[4-(2-pyrrolidinoethoxy)-phenyl]-propene; (E)- 1 ,2- dipheny 1-3 ,3 ,3 -trifluoro- 1 - [4-(2-moφholinoethoxy )-pheny 1] -propene ; (E)- 1 - [4- (2-diethylaminoethoxy)-phenyl]-l,2-diphenyl-3,3,3-trifluoro-propene; (E)-I- [4-(2-azidoethoxy)-phenyl]- 1 ,2-diphenyl-3,3,3-trifluoro-propene; (E)- 1 ,2- diphenyl-3,3,3-trifluoro-l-[4-(2-[bis-(2-chlorethyl)-amino]-etho xy)-phenyl]- propene; l-[4-(2-dimethylaminoethoxy)-phenyl]-3,3,3-trifluor-l,2-bis-(4- hydroxyph enyl)-propene; 1 -phenyl-2-(4-methoxypheny I)-I- [4-(2- dimethy laminoethoxy )pheny 1] -3 ,3 ,3 -trifluoro-propene; (E)-1 ,2-dipheny 1-3 ,3,3- trifluoro- 1 -[4-(2-[nitroguanidino]ethoxy)-phenyl]-propene; (E)- 1 -[4'(2- dimethy laminoethoxy )pheny I]- 1 -(3'-hydroxyphenyl)-b 2phenylbut- 1 -ene; (E)- 1 - [4'-(2-dimethylaminoethoxy)phenyl]- 1 -(3 '-hydroxypheny 1) -2-phenylbut- 1 - ene; (E)- 1 -[4'(2-diethylaminoethoxy)phenyl]- 1 -(3'-hydroxyphenyl)-2- phenylbut- 1 -ene; (E)- 1 -[4'-(2-diethylaminoethoxy)phenyl]- 1 -(3'- hydroxypheny 1) 2-phenylbut- 1 -ene; (E)- 1 -(3 '-hydroxyphenyl)- 1 -[4'-(2- methylaminoethoxy)phenyl]-2-phenylbut- 1 -ene; (E)- 1 (3 '-hydroxyphenyl)- 1 - [4'-(2-methy laminoethoxy)pheny 1] -2-phenylbut- 1 -ene; (E)- 1 - [4- ethy laminoethoxy )pheny 1] - 1 -(3 '-hydroxypheny l)-2-pheny lbut- 1 -ene; (E)- 1 - [4'- ethylaminoethoxy)phenyl]- 1 -)3 '-hydroxyphenyl)-2phenylbut- 1 -ene {5-[4-(l,2-Diphenyl-but-l-enyl)-phenoxy]-pentyl}-(4,4,5,5,5- pentafluoropentyl)-sulfide; {5-[4-(l,2-diphenyl-but-l-enyl)-phenoxy]-pentyl}- (4,4,5,5,5-pentafluoropentyl)-sulfoxide; (5-[4-(l,2-diphenyl-but-l-enyl)- phenoxy)-pentyl}-(4,4,5,5,5-pentafluoropentyl)-sulfone; 4-(l-{4-[5-(4,4,5,5,5- pentafluoropentylsulfidyl)-pentyloxy]-phenyl}-2-pheny l-but-l-enyl)-phenol; 4-(l-{4-[5-(4,4,5,5,5-pentafluoropentanesulfinyl)-pentyloxy]-phenyl}-2-phen yl-but-l-enyl)-phenol; 4-((E,Z)-l-{4-[5-(4,4,5,5,5- pentafluoropentanesulfonyl)-pentyloxy]-phenyl}- 2-phenyl-but-l-enyl)-phenol; (4,4,5,5,5-pentafluoropentyl)-{6-[4-((E,Z)-phenyl-l,2,3,4-tetrahydronaphth- 1- ylidenemethyl)-phenoxy]-hexyl} -sulfoxide; (3-phenylprop-2-inyl)-{5-[4- ((E,Z)-phenyl- 1 ,2,3 ,4-tetrahydronaphth- 1 -y liden emethyl)-phenoxy)-pentyl } - sulfoxide; {5-[4-((E,Z)-l,2-diphenyl-but-l-enyl)-phenoxy]-pentyl}-pyridin-2- ylmethyl-sulfoxide; {5-(4-(l,2-diphenyl-but-l-enyl)-phenoxy]-pentyl}-pyridin- 2-ylmethyl-sulfide; 4-((E,Z)-2-phenyl- 1 - {4-[5-(pyridin-2-ylmethylsulfidyl)- pentyloxy]-phenyl}-but-l-enyl)-phenol; 4-((E,Z)-2-phenyl-l-{4-[5-(pyridin-2- ylmethanesulfinyl)-pentyloxy]-phenyl}- but-l-enyl)-phenol; 4-((E,Z)-2-phenyl- l-{4-[5-(pyridin-2-ylmethanesulfonyl)-pentyloxy]-phenyl}- but-1-enyl)- phenol ; (5 - { 4- [(E5Z)- 1 -(4-iodopheny l)-2-pheny 1-but- 1 -eny 1] -phenoxy } -penty I)- (4,4, 5 , 5 , 5 -pentafluoropenty l)-sulfide; (5- { 4-((E5Z)- 1 -(4-iodopheny l)-2-pheny 1- but- 1 -eny l]-phenoxy } -penty l)-(4,4, 5 , 5,5 -pentafluoropenty l)-sulfoxide; 3 -( 1 - {4- [5 -(4,4,5 ,5 , 5 -pentafluoropenty lsulfidy l)-penty loxy]-pheny 1 } -2-pheny 1-but- 1 -eny l)-phenol ; 3 -((E5Z)- 1 - { 4- [5 -(4,4, 5 ,5 ,5-pentafluoropentanesulfiny I)- pentyloxy]-phenyl}- 2-phenyl-but-l-enyl)-phenol; (E,Z)-l-{4-[5-(4,4,5,5,5- pentafluoropentylsulfinyl)-penty loxy]phenyl } - 1 -(4- hydroxyphenyl)-2-phenyl- but-1-ene; (E)-l-{4-[5-(4,4,5,5,5-pentafluoropentylsulfinyl)-pentyloxy]- phenyl}-l-(4-h ydroxyphenyl)-2-phenyl-but-l-ene; {5-[4-((E,Z)-l,2-diphenyl- but-l-enyl)-phenoxy)-pentyl}-pyridin-2-ylmethyl-sulfone; {5-[4-(l,2-diphenyl- but-l(Z)-enyl)-phenoxy]-pentyl}-(4,4,5,5,5-pentafluorop entyl)-sulfoxide; {5- [4-( 1 ,2-dipheny 1-but- 1 (E)-enyl)-phenoxy] -penty 1 } -(4,4,5 , 5 , 5-pentafluorop enty l)-sulfoxide; 4-(l-{4-[4-(4,4,5,5,5 -pentafluoropentanesulfiny l)-buty loxy]- phenyl} -2-pheny 1-but- l(E,Z)-enyl)-phenol; 4-(l-{4-[6-(4,4,5,5,5- pentafluoropentanesulfinyl)-hexy loxy]-phenyl } -2-pheny 1-but- 1 (E,Z)-enyl)- phenol; 4-(l-{4-[(N-methyl-N-2-(4,4,5,5,5-pentafluoropentanesulfonyl)-ethyl- amino)- ethyloxy]-phenyl} -2-phenyl-but- 1 (E,Z)-enyl)-phenol; 4-( 1 -{4-(2-(N- methyl-N-2-(4,4,5,5,5-pentafluoropentanesulfinyl)-ethyl-amino )-ethyloxy]- phenyl}-2-phenyl-but-l(E,Z)-enyl)-phenol; (Z)-4-{ 12-(4,4,5,5,5- pentafluoropentylsulfinyl)- 1 -[4-(5-(4,4,5,5,5-pentaflu oropentylsulfinyl)- penty loxy )-pheny 1] -2-pheny ldodec- 1 -eny 1 } -phenol ; (E)-4- { 12-(4,4, 5 , 5 , 5 - pentafluoropentylsulfinyl)- 1 -[4-(5-(4,4,5,5,5-pentaflu oropentylsulfinyl)- penty loxy )-pheny 1] -2-pheny ldodec- 1 -eny 1) } -phenol ; N-buty l-2-(6- {4- [ 1 -(4- hydroxy-phenyl)-2-phenyl-but-l(E,Z)-enyl]-phenoxy}-he xylthio)-N- methylacetamide; N-butyl-2-(6-{4-[l-(4-hydroxy-phenyl)-2-phenyl-but- 1 (E,Z)-enyl]-phenoxy } -he xanesulfinyl)-N-methylacetamide; N-butyl-2-(6- {4- [ 1 -(4-hydroxy-phenyl)-2-phenyl-but- 1 (E,Z)-enyl]-phenoxy } -he xanesulfonyl)- N-methy lacetamide; (Z)-4- { 12-(4,4, 5 , 5 ,5 -pentafluoropenty lsulfony I)- 1 - [4-(5 - (4,4, 5 ,5 , 5-pentaflu oropenty lsulfony l)-penty loxy)-pheny 1] -2-pheny ldodec- 1 - enyl}-phenol; 4-(l-{4-[2-(4,4,5,5,5-pentafluoropentylthio)-ethyloxy]-phenyl}- 2-phenyl -but-l(E,Z)-enyl)-phenol; 4-(l-{4-[2-(4,4,5,5,5- pentafluoropentylsulfinyl)-ethyloxy]-phenyl}-2-phenyl -but-l(E,Z)-enyl)- phenol ; 4-( 1 - {4- [2-(N-methy l-N-3 -(4,4, 5 , 5 , 5 -pentafluoropenty lthio)-propy 1- amino)-et hyloxy]-phenyl}-2-phenyl-but-l(E,Z)-enyl)-phenol; 4-(l-{4-[2- (4,4,5,5,5 -pentafluoropenty lsulfony l)-ethy loxy] -phenyl } -2-pheny 1 -but- 1 (E5Z)- enyl)-phenol; 4-(l-{4-[2-(N-methyl-N-3-(4,4,5,5,5- pentafluoropentanesulfinyl)-propylamino -ethyloxy]-phenyl}-2-phenyl-but-l- (E,Z)-enyl)-phenol; 4-(3-{3-[4-(4,4,5,5,5-pentafluoropentylthio)- propy loxyjpheny 1 } -2-phenyl-but - 1 (E,Z)-eny l)-phenol ; 4-( 1 - { 4- [3 -(N-methy 1- N-2-(4,4, 5 ,5 , 5 -pentafluoropenty lthio)-ethyl-amino)-pro py loxy] -phenyl } -2- phenyl-but-l(E,Z)-enyl)-phenol; 4-(l-{4-[3-(N-methyl-N-3-(4,4,5,5,5- pentafluoropentylthio)-propyl-amino)-propy loxy] -phenyl} -2-pheny 1-but- l(E,Z)-enyl)-phenol; 4-(l-{4-[3-(4,4,5,5,5-pentafluoropentylsulfinyl)- propy loxy] -phenyl } -2-pheny 1-but- 1 (E,Z)-eny l)-phenol ; 4-(l-{4-[3 -(N-methy 1- N-2-(4,4,5,5,5-pentafluoropentanesulfinyl)-ethyl-amino )-propyloxy]-phenyl}- 2-phenyl-but-l(E,Z)-enyl)-phenol; 4-(l-{4-[3-(N-methyl-N-3-(4,4,5,5,5- pentafluoropentanesulfinyl)-propylamino -propyloxy] -phenyl} -2-pheny 1-but- l(E,Z)-enyl)-phenol; N-Butyl-2-(4-{4-[l-(4-hydroxy-phenyl)-2-phenyl-but- l(E,Z)-enyl-phenoxy}-but ylsulfinyl)-N-methylacetamide; and N-Butyl-2-(4- (4-[l-(4-hydroxy-phenyl)-2-phenyl-but-l(E,Z)-enyl-phenoxy}-pentylsulfinyl)- N-methylacetamide.
Toremifene
Toremifene has the following structure:
Figure imgf000074_0001
Analogs of toremifene are described by Formulas (1) and (2) in U.S. Patent No. 4,696,949 and Formula (1) in EP 1475087. Exemplary analogs of toremifene are: 1 -phenyl- l,2-bis(4- hydroxyphenyl)- 1 -buten-4-ol; 4-bromo- 1 -phenyl- 1 ,2-bis(4-hydroxyphenyl)- 1 - butene; 2-phenyl-2,3-bis(4-hydroxyphenyl)tetrahydrofuran; 1 ,2-diphenyl- 1 -(4- hydroxyphenyl)-l-penten-5-ol; 2,3-diphenyl-2-(4- hydroxyphenyl)tetrahydropyran; 1 ,2-dipheny 1- 1 -(4-hydroxyphenyl)- 1 -penten- 5-al; 1,2-diphenyl-l -(4-hydroxyphenyl)- 1 -buten-4-ol; 2,3-diphenyl-2-(4- hydroxyphenyl)tetrahydrofuran; 1 ,2-diphenyl- 1 -[4-[2-(N5N- dimethylamino)ethoxy]phenyl]- 1 -buten-4-ol; 4-chloro- 1 ,2-diphenyl- 1 -[4-[2- (N,N-dimethylamino)ethoxy]phenyl]- 1 -butene; 4-chloro- 1 ,2-diphenyl- 1 -[4-[2- (1 -aziridiny l)ethoxy]phenyl]- 1 -butene; 4-bromo- 1 ,2-diphenyl- 1 - [4- [2-( 1 - pyrrolidinyl)ethoxy]phenyl]- 1 -butene; 2,3-diphenyl-2-[4-[2-(N,N- diethylamino)ethoxy]phenyl]tetrahydrofuran; 1 -phenyl- 1 ,2-bis(4- hydroxyphenyl)butan-4-ol; 4-bromo- 1 -phenyl- 1 ,2-bis(4- hydroxyphenyl)butane; 1 ,2-diphenyl- 1 -(4-hydroxyphenyl)butan-4-ol; 4-chloro- 1 ,2-diphenyl- 1 -[4-(2-piperidinoethoxy)phenyl]butane; 1 ,2-diphenyl- 1 -(4- hydroxyphenyl)butane- 1 ,4-diol; 1 -phenyl- 1 ,2-bis(4-hydroxyphenyl)butane- 1 ,4- diol; 1 ,2-diphenyl- 1 -(4-methoxypheny I)- 1 -buten-4-ol; 4-bromo- 1 ,2-diphenyl- 1 - [4-[2-(N,N-dimethylamino)ethoxy]phenyl]- 1 -butene; 4-chloro- 1 ,2-diphenyl- 1 - (4-hydroxypheny l)butane; 4-chloro- 1 ,2-diphenyl- 1 -(4-hydroxyphenyl)- 1 - butene; and 1 ,2-diphenyl- l-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butane- 1,4-diol.
IKK-β Inhibitors
The IKB kinase (IKK) protein complex has two catalytic subunits, DCK- α and DCK-β (also known as DCK-2). Inhibitors of IKK-β are useful in the compositions, methods and kits of the invention. IKK-β inhibitors are described by: Formulas (I), (II), (III), and (IV) in U.S. Patent Nos. 5,939,421 and 6,150,372; Formulas (I) and (II) in U.S. Patent Nos. 6,627,637 and 7,026,331; Formulas (I) and (If) and Compound 6 in WO2002060386 and U.S. Patent No. 6,869,956; Formula (I) and (If) in U.S. Patent No. 6,960,585; U.S. Patent Publication No. 20040024047; Formula (I) and the compounds recited in paragraphs [0077]-[0088], [0096]-[0112], and [0114]-[0188] in U.S. Patent Publication No. 20060030596; Formulas (I), (IIA-C), (IIIA-M), (S-IIIA'), (IIIA-a), (IIIA-aa), and compounds (l)-(106) in U.S. Patent Publication
20040235839; Formulas (I), (IIA-E), (IIIA), (HIA'), (IIIA-a), (IIIA-aa), (IIIF- M), (IIIA), and compounds (l)-(207) in U.S. Patent Publication No. 20050239781 ; Formulas (I), (Ia), and (Ib) and the compounds included in Table 1 in U.S. Patent Publication 20070207997; WO2008002246; WO2002030353; WO2003029242; WO2003010163; WO2001058890; WO2002044153; WO2002024679; WO2003076447; WO2001030774; WO2001000610; WO2003024936; WO2003024935; WO2002041843; WO2002030423; WO2002094265; and WO2002094322, all of which are hereby incorporated by reference Exemplary IKK-β inhibitors include but are not limited to: MLN0415 ;
AS602868;N-(6-Chloro-9H-β-carbolin-8-yl)-nicotinamide, as well as the bismesylate, bistrifluoroacetate, and the bishydrochloride salts thereof; N-(6- chloro-9H-β-carbolin-8-yl)-3, 4-difluoro-benzamide, and the hydrochloride salt thereof; N-(6-chloro-7-methoxy-9H-β-carbolin-8-yl)-nicotinamide, and the bistrifluoracetate and bishydrochloride salts thereof; 6-chloro-N-(6-chloro-9H- β -carbolin-8-yl)-nicotinamide; l-methyl-4-methylaminobenzo[g]imidazo[l ,2- ajquinoxaline; 1 -methyl-4-(2-N-methylaminoethylamino)benzo[g]imidazo[ 1 ,2- ajquinoxaline hydrochloride; 1 -methyl-4-methylaminobenzo[g]pyrazolo[ 1,5- c]quinazoline; 1 -methyl-4-(2-N-methylaminoethylamino)benzo[g]pyrazolo [l,5-c]quinazoline; l-methyl-4-methylaminobenzo(g)imidazo(4,5-c)quinoline; l-methyl-4-(2-N-methylaminoethylamino)benzo(g)imidazo(4,5-c)quinoline; 1- methyl-4-(2-hydroxyethylamino)benzo[g]imidazo[l,2-a]quinoxaline; 1-methyl- 4-(2-piperidin- 1 -yl-ethylamino)benzo[g]imidazo[ 1 ,2-a]quinoxaline; Additional exemplary IKK-β inhibitors include:
Figure imgf000077_0001
Figure imgf000078_0001
IMD-0354
IMD-0354 is an IKK-β inhibitor and has the following structure:
Figure imgf000078_0002
Analogs of IMD-0354 include other small molecule NF-κB inhibitors. Exemplary small molecule NF-κB inhibitors are: antioxidants; SP 100030; dehydroxymethylepoxyquinomicin (DHMEQ); Formula (I) in WO2006/032322, hereby incorporated by reference. Analogs of IMD-0354 are also described by the following formula
Figure imgf000078_0003
wherein, independently, X is halogen at any position of the ring; X is O or X; R1, R2, R3, R4, and R5 are H or perhalogenated C1-6 alkyl; and R6 is H or Ci-6 alkyl.
Additional Agents Alverine
Alverine has the following structure:
Figure imgf000079_0001
Structural analogs of alverine are described by the following formula
Figure imgf000079_0002
wherein, independently, R1 is H or C1-6 alkyl; R2, R3, R4, R5, R6, R7, R8, R9, Rj0, and Rn are selected from H, halogen, OH, C1-6 alkyl, and OC1-6 alkyl; m is 0, 1, 2, 3, 4, 5, or 6; and n is 0, 1, 2, 3, 4, 5 or6.
Λmiodarone
Amiodarone has the following structure:
Figure imgf000079_0003
Structural analogs of amiodarone are described by the general formula and Examples I, II, and III found in U.S. Patent No. 3,248,401; the general formula in U.S. Patent No. 5,849,788 (see, for example, claim 1); the compounds disclosed in U.S. Patent No. 5,567,728; and Formula (I) in U.S. Patent No. 4,851,554. Additional analogs of amiodarone are found in U.S. Patent Nos. 7,148,240; 6,515,147; 6,316,487; and 5,981,514. Exemplary structural analogs of amiodarone are: 3,5-diiodo-4-(2-N,N- diethylaminoethoxy)phenyl-(2-butylbenzofur-3-yl)methanol hydrochloride; 2- methyl-3-(3,5-diiodo-4-(2-N,N-diethylamino-ethoxy)-benzoyl)benzofuran hydrochloride; 2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy- benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran; 2-methyl-3-(3,5-diiodo-4-carboxymethoxy-benzyl)benzofuran; 4'-hydroxy-3'- iodo-3,5 diiodo-4-(2-N,N-dimethylamino-ethoxy)benzophenone hydrochloride; 2-butyl-3-(3-iodo-4-hydroxybenzoyl)benzofuran; and 4',4-dihydroxy-3'3,5- triiodo-diphenylmethane.
Chloroquine and Hydroxychloroquine
Chloroquine has the following structure:
Figure imgf000080_0001
Hydroxychloroquine has the following structure:
Figure imgf000081_0001
Structural analogs of chloroquine and hydroxychloroquine are described in U.S. Pat. No. 2,233,970, or have the following structure:
Figure imgf000081_0002
wherein, independently, X is H or halogen; Ri, R2, R3, R4, and R5 are selected from H, halogen, Ci-6 alkyl, OH, OCi-6 alkyl, CN, or NO2; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; R6, R7, Rg, and R9 are H, Ci-6 alkyl, or (CH2)n(CH2OH) where n is 0, 1, 2, 3, 4, or 5.
Chlorprothixene
Chlorprothixene has the following structure:
Figure imgf000081_0003
Structural analogs of chlorprothixene have the following structure:
Figure imgf000082_0001
wherein, independently, R1, R2, R3, R4, R5, R6, R7, Rs, and R9, are each selected from H, halogen, C1-6 alkyl, perhalogenated Ci-6 alkyl, OH, OC1-6 alkyl, OCF3, SH, SCi-6 alkyl, or SCF3, wherein at least one OfR1-R8 is a halogen; Y is CH2, O, NH, S(O)0-2, (CH2)3, (CH)2, CH2O, CH2NH, CHN, or CH2S; A is a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; Bi and B2 are selected from H, perhalogenated C1-6 alkyl, C1-6 alkyl, or Bi and B2 join together to form an optionally substituted ring.
Dicyclomine
Dicyclomine has the following structure:
Figure imgf000082_0002
Structural analogs of dicyclomine are described in U.S. Patent No. 2,474,796. Structural analogs of dicyclomine are also described by the following formula
Figure imgf000082_0003
wherein, independently, n is 1, 2, 3, 4, 5 ,or 6; X and Y are selected from O and S; and Ri and R2 are H or Ci-6 alkyl. Hexachlorophene
Hexachlorophene has the following structure:
Figure imgf000083_0001
Structural analogs of hexachlorophene are described by the formula
Figure imgf000083_0002
wherein, independently, X1, X2, X3, X4, X5, and X6 are H or halogen and n is O, 1, 2, 3, 4, or 5.
Metergoline
Metergoline has the following structure:
Figure imgf000083_0003
Structural analogs of metergoline are described by Formula (I) of U.S. Patent No. 3,238,211.
Nitazoxanide
Nitazoxanide has the following structure:
Figure imgf000084_0001
Structural analogs of nitazoxanide include tizoxanide or have the following structure:
Figure imgf000084_0002
wherein, independently, R1 and R2 are selected from H, halogen, CN, NO2, CF3, or Ci-6 alkyl; R3 is H or Ci-6 alkyl; R4, R5, R6, R7, and R8 are selected from H, halogen, CN, NO2, CF3, Ci-6 alkyl, or OCj-6 alkyl; X, Y, and Z is selected from O, S, or NR9; A is a bond, O, S, or NR9; R9 is H or Ci-6 alkyl; and B is H or C(Z)-X-R8.
Thioridazine
Thioridazine has the following structure:
Figure imgf000084_0003
Structural analogs of thioridazine have the structure
Figure imgf000085_0001
wherein, independently, Ri, R2, R3, R4, R5, R6, R7, and Rg are each selected from H, halogen, C1-6 alkyl, perhalogenated Ci-6 alkyl, OH, OCi-6 alkyl, OCF3, SH, SC,-6 alkyl, or SCF3; Y is CH2, O, NH, S(O)0-2, (CH2)3, (CH)2, CH2O, CH2NH, CHN, or CH2S; A is a bond or a branched or unbranched, saturated or monounsaturated hydrocarbon chain having between 1 and 6 carbons, inclusive; each Bi, B2, B3, and B4 is, independently, H, halogen, perhalogenated Ci-6 alkyl, Ci-6 alkyl, OCi-6 alkyl, O(perhalogenated OCi-6 alkyl), or B1 and B2, Bi and B3, B1 and B4, B2 and B3, B2 and B4, or B3 and B4 join together to form an optionally substituted ring.
Thioridazine analogs are also described by Formulas (I), (IIA), and (IIB) in U.S. Application Publication No. 2007-0287702.
Vanoxerine
Vanoxerine has the structure:
Figure imgf000085_0002
Structural analogs of vanoxerine are described by Formula (I) in U.S. Patent No. 4,202,896; Formula (I) in U.S. Patent No. 4,476,129; and Formula (I) in U.S. Patent No. 4,874,765. Additional Therapeutic Regimens
If desired, the patient may also receive additional therapeutic regimens. For example, therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective for such therapeutic agents. Agents that may be particularly useful include those that prevent or slow the rate of neural deterioration or death, or those that treat, prevent, or ameliorate one or more symptoms of a neurodegenerative disorder. Exemplary therapeutic classes and agents are listed in Table 2. Combinations of the classes and agents of Table 2 may also be used. If more than one agent is employed, therapeutic agents may be delivered separately or may be admixed into a single formulation. When agents are present in different pharmaceutical compositions, different routes of administration may be employed. Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (e.g., intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration). Alternatively, agents may be administered by intracranial, intrathecal, or epidural administration. Any method of administration that bypasses the blood-brain barrier or enhances its permeability (e.g., administration of a NaVCa+* exchange blocker, mannitol, or Cereport) may be useful.
In some instances, an agent and additional therapeutic agents are administered at least one hour, two hours, four hours, six hours, 10 hours, 12 hours, 18 hours, 24 hours, three days, seven days, or 14 days apart. The dosage and frequency of administration of each component of the combination can be controlled independently. For example, one compound may be administered three times per day, while the second compound may be administered once per day. Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects. The compounds may also be formulated together such that one administration delivers both compounds. Optionally, any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein. The therapeutic agents may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers. A pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions described herein to a patient. Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds, described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
In addition to the administration of therapeutic agents, the additional therapeutic regimen may involve other therapies, e.g., transplantation of neural cells (including, if needed, anti-inflammatory and/or immunosuppressive therapy), or a modification to the lifestyle of the patient being treated.
Conjugates
If desired, the drugs used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula I.
(A)-(L)-(B) (I)
In formula I, (A) is an agent listed in Table Ia or Ib covalently tethered via a linker (L) to (B), any agent of the classes and agents listed in Tables Ia, Ib, and 2.
Conjugates can be administered to a subject by any route and for the treatment of any disease described herein. The conjugates can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases). The conjugates can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate.
Conjugates can be prepared using techniques familiar to those skilled in the art. For example, the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996. The synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B). For example, commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m- nitrophenyl. Other commonly used protecting groups for amines include amides, such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert- butylsulfonyl amides. Examples of commonly used protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2- (trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho- esters, and halo-esters. Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P- nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy- trityls), and silyl ethers. Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls. In addition, sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides). Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule. The conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd Ed.), John Wiley & Sons, 1991 and PJ. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
Linkers
The linker component is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
Thus, linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B). Examples of chemically reactive functional groups which may be employed for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
The covalent linking of drug (A) and drug (B) may be effected using a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B). For example, an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an amide linking the two.
Examples of moieties capable of reaction with sulfhydryl groups include α-haloacetyl compounds of the type XCH2CO- (where X=Br, Cl or I), which show particular reactivity for sulfhydryl groups, but which can also be used to modify imidazolyl, thioether, phenol, and amino groups as described by Gurd, Methods Enzymol 11 :532 (1967). N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions. Reagents such as 2- iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents. Representative alkylating agents include:
(i) α-haloacetyl compounds, which show specificity towards amino groups in the absence of reactive thiol groups and are of the type XCH2CO- (where X=Cl, Br or I), for example, as described by Wong Biochemistry 24:5337 (1979);
(ii) N-maleimide derivatives, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group, for example, as described by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J. 91 :589 (1964); (iii) aryl halides such as reactive nitrohaloaromatic compounds;
(iv) alkyl halides, as described, for example, by McKenzie et al., J. Protein Chem. 7:581 (1988);
(v) aldehydes and ketones capable of Schiff s base formation with amino groups, the adducts formed usually being stabilized through reduction to give a stable amine;
(vi) epoxide derivatives such as epichlorohydrin and bisoxiranes, which may react with amino, sulfhydryl, or phenolic hydroxyl groups;
(vii) chlorine-containing derivatives of s-triazines, which are very reactive towards nucleophiles such as amino, sufhydryl, and hydroxyl groups; (viii) aziridines based on s-triazine compounds detailed above, e.g., as described by Ross, J. Adv. Cancer Res. 2: 1 (1954), which react with nucleophiles such as amino groups by ring opening;
(ix) squaric acid diethyl esters as described by Tietze, Chem. Ber. 124: 1215 (1991); and
(x) α-haloalkyl ethers, which are more reactive alkylating agents than normal alkyl halides because of the activation caused by the ether oxygen atom, as described by Benneche et al., Eur. J. Med. Chem. 28:463 (1993).
Representative amino-reactive acylating agents include: (i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives respectively;
(ii) sulfonyl chlorides, which have been described by Herzig et al., Biopolymers 2:349 (1964);
(iii) acid halides; (iv) active esters such as nitrophenylesters or N-hydroxysuccinimidyl esters;
(v) acid anhydrides such as mixed, symmetrical, or N- carboxy anhydrides ;
(vi) other useful reagents for amide bond formation, for example, as described by M. Bodansky, Principles of Peptide Synthesis, Springer- Verlag, 1984;
(vii) acylazides, e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal. Biochem. 58:347 (1974); and (viii) imidoesters, which form stable amidines on reaction with amino groups, for example, as described by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962).
Aldehydes and ketones may be reacted with amines to form Schiff s bases, which may advantageously be stabilized through reductive amination. Alkoxylamino moieties readily react with ketones and aldehydes to produce stable alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1 :96 (1990).
Examples of reactive moieties capable of reaction with carboxyl groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv. Protein Chem. 3:169 (1947). Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed. It will be appreciated that functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as α -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2- bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
So-called zero-length linkers, involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used.
Most commonly, however, the linker will include two or more reactive moieties, as described above, connected by a spacer element. The presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two. The reactive moieties in a linker may be the same (homobifunctional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
Spacer elements in the linker typically consist of linear or branched chains and may include a C1-Ci0 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C6 heterocyclyl, C6-C]2 aryl, C7-C14 alkaryl, C3-Ci0 alkheterocyclyl, or C1-C10 heteroalkyl. In some instances, the linker is described by formula (II):
G1-(Z1)o-(Y1)u-(Z2)s-(R30)-(Z3)t-(Y2)v-(Z4)p-G2 (II)
In formula (II), G1 is a bond between drug (A) and the linker; G2 is a bond between the linker and drug (B); Z1, Z2, Z3, and Z4 each, independently, is selected from O, S, and NR31; R31 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C2-C6 heterocyclyl, C6-C12 aryl, C7-C14 alkaryl, C3-C10 alkheterocyclyl, or C1-C7 heteroalkyl; Y1 and Y2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, and phosphoryl; o, p, s, t, u, and v are each, independently, 0 or 1; and R30 is a C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C6 heterocyclyl, C6-C12 aryl, C7-C14 alkaryl, C3-C10 alkheterocyclyl, or C1-C10 heteroalkyl, or a chemical bond linking G^(Z1V
(Y1V(Z2V to -(Z3MY2V(Z4V-G2.
Examples of homobifunctional linkers useful in the preparation of conjugates include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and polycaprolactone diol. Formulation
Any of the agents described herein may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).
If more than one agent is employed, each agent may be formulated in a variety of ways that are known in the art. Desirably, the agents are formulated together for the simultaneous or near simultaneous administration of the agents. Such co-formulated compositions can include the two agents formulated together in the same pill, capsule, liquid, etc. It is to be understood that, when referring to the formulation of such combinations, the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations described herein. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be suitably matched.
The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients ("bulk packaging"). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.
Formulations and Methods for Delivery of Agents to the Brain
Treatment of neurodegenerative disorders, e.g., HD, may be hampered by the inability of an active, therapeutic compound to cross the blood-brain barrier (BBB). Strategies for delivery of compositions described herein to the brain include strategies to bypass the BBB (e.g., intracranial administration via craniotomy and intrathecal administration), and strategies to cross the BBB (e.g., the use of compounds that increase permeability of the BBB in conjunction with systemic administration of compositions described herein, and modification of compositions described herein to increase their permeability or transport across the BBB).
Craniotomy, a procedure known in the art, can be used with any composition described herein for delivery to the brain. In this approach, an opening is made in the patient's cranium, and a compound is delivered via a catheter. This approach can be used to target a compound to a specific area of the brain.
Intrathecal administration provides another means of bypassing the BBB for drug delivery. Briefly, drugs are administered to the spinal chord, for example, via lumbar puncture or through the use of devices such as pumps. Lumbar puncture may be used for single or infrequent administration, whereas constant and/or chronic administration may be achieved using any commercially available pump attached to a intraspinal catheter, e.g., a pump and catheter made by Medtronic (Minneapolis, Minn.). To allow for delivery across the BBB, compositions described herein can be administered along with a compound or compounds that induce a transient increase in permeability of the BBB. Such compounds include mannitol, Cereport (RMP-7), and KB-R7943, a Na+ZCa4"1" exchange blocker. Compounds described herein can be modified (e.g., lipidated or acetylated) to increase transport across the BBB following systemic administration (e.g., parenteral) by using chemical modifications that are standard in the art. In some embodiments, compounds described herein are conjugated to peptide vectors that are transported across the BBB. For example, compounds may be conjugated to a monoclonal antibody to the human insulin receptor as described by Partridge (Jpn. J. Pharmacol. 87:97- 103, 2001), thus permitting the compound to be transported across the BBB following systemic administration. Compounds described herein can be conjugated to such peptide vectors, for example, using biotin-streptavidin technology.
Dosages
Generally, when administered to a human, the dosage of any of the agents of the combinations described herein will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2,000 mg per day, about 1 mg to 1,000 mg per day, or about 5 mg to 500 mg per day.
Administration of each drug in the combination can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases. Additional Applications
If desired, compounds may be employed in mechanistic assays to determine whether other combinations, or single agents, are as effective as the combination in treating, preventing, or ameliorating neurodegenerative disorders (e.g., HD or any of its associated conditions) using assays generally known in the art, examples of which are described herein. For example, candidate compounds may be tested, alone or in combination with one or more compounds selected independently from any of the agents of Tables Ia and Ib, and applied to cells, e.g., neural cells or mouse striatal knock-in cell line STHdhQ 111 expressing a toxic mutant polyglutamine repeat protein. After a suitable time, these cells are examined for immunoreactivity using the polyQ antibody, 1F8. A decrease in perinuclear staining, in comparison to control cells not treated with the candidate compound, identifies a candidate compound or combination of agents as an effective agent to treat, prevent, or ameliorate a neurodegenerative disorder.
The agents described herein may also be useful tools in elucidating mechanistic information about the biological pathways involved in neural cell deterioration and death. Such information can lead to the development of new combinations or single agents for treating, preventing, or ameliorating neurodegenerative disorders. Methods known in the art to determine biological pathways can be used to determine the pathway, or network of pathways, affected by contacting cells, e.g., neural cells, with the compounds described herein. Such methods can include analyzing cellular constituents that are expressed or repressed after contact with the compounds described herein as compared to untreated, positive or negative control compounds, and/or new single agents and combinations, or analyzing some other activity of the cell such as enzyme activity, nutrient uptake, and proliferation. Cellular components analyzed can include gene transcripts and protein expression. Suitable methods can include standard biochemistry techniques, radiolabeling the compounds described herein (e.g., 14C or Η labeling), and observing the compounds binding to proteins, e.g. using 2D gels, gene expression profiling. Once identified, such compounds can be used in in vivo models to further validate the tool or develop new agents or strategies to treat, prevent, or ameliorate neurodegenerative disorders.
As indicated above, the methods described herein may also be used prophylactically, in patients who are at an increased risk of developing a neurodegenerative disorder, e.g., HD, or a condition associated with such a disorder. Risk factors include, for example, age, family history of neurodegenerative disorders, and psychological or psychiatric profile.
Exemplary Candidate Compounds Peptide Moieties
Peptides, peptide mimetics, and peptide fragments (whether natural, synthetic or chemically modified) may be suitable for use. Exemplary compounds include those that reduce the amount of target protein or RNA levels (e.g., antisense compounds, dsRNA, ribozymes) and compounds that compete with endogenous mitotic kinesins or protein tyrosine phosphatases for binding partners (e.g., dominant negative proteins or polynucleotides encoding the same).
Antisense Compounds
The biological activity of any protein that increases cell death, e.g., mutant Htt, can be reduced through the use of an antisense compound directed to RNA encoding the target protein. Antisense compounds that reduce expression of target molecules can be identified using standard techniques. For example, accessible regions of the mRNA of the target enzyme can be predicted using an RNA secondary structure folding program such as MFOLD (M. Zuker, D. H. Mathews & D. H. Turner, Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO ASI Series, Kluwer Academic Publishers, (1999)). Sub-optimal folds with a free energy value within 5% of the predicted most stable fold of the mRNA are predicted using a window of 200 bases within which a residue can find a complimentary base to form a base pair bond. Open regions that do not form a base pair are summed together with each suboptimal fold and areas that are predicted as open are considered more accessible to the binding to antisense nucleobase oligomers. Other methods for antisense design are described, for example, in U.S. Patent No. 6,472,521, Antisense Nucleic Acid Drug Dev. 1997 7:439-444, Nucleic Acids Research 28:2597-2604, 2000, and Nucleic Acids Research 31 :4989-4994, 2003.
RNA Interference The biological activity of a target molecule can be reduced through the use of RNA interference (RNAi), employing, e.g., a double stranded RNA (dsRNA) or small interfering RNA (siRNA) directed to the target molecule in question (see, e.g., Miyamoto et al., Prog. Cell Cycle Res. 5:349-360, 2003; U.S. Patent Application Publication No. 20030157030). Methods for designing such interfering RNAs are known in the art. For example, software for designing interfering RNA is available from Oligoengine (Seattle, WA).
Dominant Negative Proteins
One skilled in the art would know how to make dominant negative proteins to the target molecules to be targeted. Such dominant negative proteins are described, for example, in Gupta et al., J. Exp. Med., 186:473-478, 1997; Maegawa et al., J. Biol. Chem. 274:30236-30243, 1999; Woodford- Thomas et al., J. Cell Biol. 117:401-414, 1992). The following examples are provided for the purpose of illustrating the invention and are not meant to limit the invention in any way.
Example 1: Screening Assays Provided are screening methods for identifying candidate compounds that treat, prevent, or ameliorate neurodegenerative disorders, e.g., HD.
A variety of model systems, including cellular as well as animal models, have demonstrated that the exon 1 portion of Htt, containing an expanded polyglutamine region, is sufficient to cause pathology. For example, the STHdhQl 11 cell line derived from the HD knock-in mouse model, which expresses mutant Htt at endogenous level with the right genetic context, has been widely used and well characterized. This cell line recapitulates many HD pathogenic features, such as mitochdria dysfunction and energy deficiency, and thus is regarded as one of the most HD-relevant cellular models. In order to perform screening, an ICC image-based high content screening (HCS) assay has been developed and optimized on Cellomics Array Scan VTi, using the polyQ antibody 1F8 and the STHdhQl 11 cell line. Multiple HD-relevant endpoints have been identified which can differentiate the mutant STHdhQl 11 cell line from its wild-type counterpart STHdhQl, and the primary endpoint used in this assay is the perinuclear staining by the 1F8 antibody. The goal of the screening is to identify single agents as well as combinations of agents that decrease the intensity of perinuclear staining by the 1F8 antibody in the STHdhQl 11 cell line. In addition, information about cell density is collected after the drug treatment to monitor the cytotoxicity caused by the drug treatment.
Assay performance was evaluated by looking at a variety of parameters, e.g., Z' factors (described below), plate-to-plate variations, and performance of the positive control compound hexachlorophene (15 μM). The following formulas were used to calculate inhibition of perinuclear staining of the 1F8 antibody by tested compounds:
• % of inhibition = [(DMSO treated-compound treated)/DMSO treated] 100 More than 50% of killing was consistently achieved 72 hours following hexachlorophene treatment when comparing with DMSO-treated wells. For single-agent ranking, the assay was performed in 384-well plates to obtain duplicate dose response curves in 12-step dilutions with a dosing ratio f = 2 over 3 orders of magnitude. Single agent activity was characterized by fitting a sigmoidal function of the form I = ImaxCα/[Cα+EC5oα], with least squares minimization using a downhill simplex algorithm (C is the concentration, EC5O is the agent concentration required to obtain 50% of the maximum effect, and α is the sigmoidicity). The uncertainty of each fitted parameter was estimated from the range over which the change in reduced chi-squared was less than one, or less than minimum reduced chi-squared if that minimum exceeded one, to allow for underestimated σi errors.
Single agent curve data were used to define a dilution series for each compound to be used for combination screening in a 6x6 matrix format. Using a dilution factor f of 2, 3, or 4, depending on the sigmoidicity of the single agent curve, five dose levels were chosen with the central concentration close to the fitted EC50. For compounds with no detectable single agent activity, a dilution factor of 4 was used, starting from the highest achievable concentration. Combination effects can be most readily characterized by comparing each data point's inhibition to that of a combination reference model that was derived from the single agent curves. Two models were used to quantify combination effects: (1) The highest single agent (HSA) model /HSA(CX,CY) = max(lχjγ) is a simple reference model where Cjςy are the concentrations of the X and Y compound, and Ix^ are the inhibitions of the single agents at Cx^; and (2) Loewe additivity, where /LOeWe(C1 X5Cv) is the inhibition that satisfies (Cx/ECχ) + (Cγ/ECγ) = 1, and ECx^ are the effective concentrations at /Loewe for the single agent curves. Loewe additivity is a generally accepted reference for synergy, as it represents the combination response generated if X and Y are the same compound. /HSA is easily calculated from /X)Y, but determining /Loewe requires interpolation and numerical root finding.
Combinations were ranked initially by HSA Excess Volume, then by the ADD Excess Volume. A "Synergy Score" was also used, where the Synergy Score S = log fx log fγ ∑ Idata (Idata- lLoewe)> summed over all non-single-agent concentration pairs, and where log fχ,γ is the natural logarithm of the dilution factors used for each single agent. This effectively calculates a volume between the measured and Loewe additive response surfaces, weighted towards high inhibition and corrected for varying dilution factors. An uncertainty σ§ was calculated for each synergy score, based on the measured errors for the Idata values and standard error propagation.
To select desirable combinations for follow-up characterization, the following criteria were established: (1) significant synergy over the additive model as measured by the HSA Volume with a cut-off value = 0.5; (2) substantial activity where the synergy occurs and/or sufficient potency shifting, with a maximum effect greater or equal to 50% for combinations.
Based upon the combination screen, the combination agents listed in Table 3 a were identified.
After plates were read, the raw data were analyzed, and automated quality control criteria were used to assess the quality of the data from each plate based on the control data contained in the plate. The automated analysis first determined plates to be verified, rejected or undetermined. All plates were then evaluated manually on a plate-by-plate basis and, if necessary, assigned a status of hand accepted or rejected. Additionally, individual blocks of data on verified plates could be manually marked for exclusion.
The quality control criterion for automated analysis was called the Z'- factor, which is defined as:
7, _ 1 3 SD of DMSO + 3 SD of control |median DMSO - median of control|
Here, SD represents standard deviation, and DMSO represents vehicle treated. Control represents the background which is defined by wells undergoing all the assay procedures but without the secondary antibody.
Based on the Z'-factor, automated quality control marked a plate as verified (Z' > 0.3), rejected (Z'<0.3 or Z'>1). Plates that were rejected either automatically or by visual inspection were excluded from further analysis and were scheduled to be repeated.
In addition to manually verifying plates with marginal Z' -factors, all plates were visually inspected for occasional bad wells, or "spikes." Individual wells with data values that were very different from their immediate neighbors (within the same treatment class) were flagged and excluded from subsequent analyses. Plates containing an unusually large number of spikes were rejected altogether.
The data show that the ICC-based HCS assay using STHdhQl 11 cells and the 1F8 antibody performed quite well with excellent Z' scores (between 0.3 and 0.8) with very small plate-to-plate variations.
The cut-off for hit picking was chosen to be 20% inhibition of perinuclear staining by the 1F8 antibody. All compounds that gave at least 20% inhibition for at least one dose were included. Hits from the ranking experiments are shown in Tables Ia and Ib. A detailed protocol for the ICC Cellomics assay follows. Protocol for Cellomics-ICC Assay Using Mouse Striatal Cell Lines
Day 1- seed cells and add compounds
1. Make a complete DMEM medium containing
10% FBS, ^ penicillin/streptomycin,
0.4 mg/ml G418,
2. Warm up medium and 0.25% trypsin-EDTA to 33°C in water bath
3. Aspirate old medium and wash once with 25ml PBS 4. Add 7 ml 0.25% trypsin-EDTA to the Tl 75 flask and sit for 5
~ 6 min, rock gently at 2~3min, ensure all cells are dissociated
5. Add 8 ml of the medium to the flask to inactivate trypsin
6. Pipette cells several times ensure that cells are well dissociated
7. Spin down at lOOOrpm for 5min 8. Resuspend in 5 ml (per flask) complete medium and triturate
9. Count cells with hemacytometer or Cellometer
10. Make a final cell solution at a density of 178000 cells/ml and seed 45 μl (8,000) cells/well into 384-well plates using multidropper 11. Put plates in the 330C incubator for ~2hrs, try not to stack plates
12. Remove compound plates from desiccators
13. Using the PlateMate, prepare dilution plates with 100 μl per well of the complete cell medium at room temperature in clean 384 well plates
14. Using the MiniTrak, make compound dilution plates, 1 μl from each well of stock plates, into 100 μl of media in the dilution plate for a 1 : 100 dilution (10X stock in media). Add 5 μl of the diluted stock to each well of cells in assay plates 15. Incubate plates at 330C for overnight (~24hr) Day 2- cell fixation, permeabilization and primary antibody staining 1. Prepare the following fresh or stock solution:
5% BSA in PBS 5% Triton X-100 in PBS IM Glycine (0.75%) in PBS PBS+ (PBW with 0.5% BSA and 0.15% Glycine) 4% Formaldehyde-MeOH free in PBS (freshly diluted from 16% stock) 0.5% Triton X-100 in PBS (fresh diluted)
2. Fix with 4% FA for 15 min. Prime multidropper with 4% FA, Prime Biotek autowash with 100 ml PBS, set as IX wash with 60 ul PBS with final aspirartion, do the following one plate at a time: i. Aspirate ii. Add 4% FA 60ul/well iii. Incubate 15min at RT
(10 plates can be optimally staggered this way, with plenty of time to prepare autowash and multidrop for next steps. Split plates to batches when handling >10 plates.)
3. Set the autowash program as 2X wash (60 ml PBS/well) with final aspiration, prime the multi-dropper with 50ml 0.5% Triton X-100 4. Do the following one plate at a time, 10 plates per batch: i. Wash 2X with PBS, aspirate ii. Add 0.5% Triton X-100 60 ml/well iii. Start to count time, incubate each plate with PBS/ 0.5% Triton X-100 for 15 min, and process the next plate 5. Change the autowash program to 2x wash with aspiration, prime the multidropper with PBS+, do the following one plate at a time i. Wash 2X with PBS, aspirate ii. Add PBS+ 60 ml/well iii. Incubate at RT > 30min (allowing a long break)
6. Dilute primary antibody (1 :2000 for 1F8) in PBS+
7. Prime multidrop with 10ml primary antibody, set autowash to aspiration 8. Aspirate and add primary antibody 40 ml/well to column 1—23, manually add 40 ml/well PBS+ to column 24
9. Incubate with primary antibody at RT for lhr with gentle rocking, wrap plates in plastic wrap, and incubate overnight at 4°C Day 3- secondary antibody incubation and Cellomics array scanning
10. Warm up plates by gently rocking 30min ~lhr at RT
11. Set autowash as aspiration, prime multidrop with PBS. Do the following one plate at a time: i. Aspirate ii. Add PBS 60 ml/well iii. Incubate at RT >5 min (5~15min) Repeat twice
12. Prepare secondary antibody (l :500)/Hoechst 33342 (1 :1000) in PBS+ 13. Prime multidrop with secondary antibody. Do the following one plate at a time: i. Aspirate ii. Add diluted secondary antibody 40ml/well iii. Incubate at RT >1 hr (allowing a long break) 14. Set autowash as aspiration, prime multidrop with PBS. Do the following one plate at a time: i. Aspirate, ii. Add PBS 60 ml/well iii. Incubate at RT >5 min (5~15min)
Repeat above wash twice with final PBS in the wells
15. Seal with hot seal or aluminum seal
16. Scan plates with Cellomic Array ScanVTi. Scan could go overnight using Twister II. Day 4: Export data to platemanager and analyzer
The screening methods described herein may be varied. For example, any cell line expressing a CAG repeat gene containing an expanded CAG repeat region may be used. Screening assays directed to a given polyglutamine repeat disorder may be varied, e.g., by utilizing a cell line expressing a polyglutamine repeat protein, or fragment thereof, associated with that disorder. Any cutoff for hit picking may be chosen, e.g., 1%, 2%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In addition, any method of assaying cell viability may be employed.
Example 2: Further Screening Assay: Protocol for TMRE Assay Using Mouse Striatal Cell Lines
Provided is a further screening method for identifying candidate compound pairs that treat, prevent, or ameliorate neurodegenerative disorders, e.g., HD. This method was used to screen pairs of compounds, each of which was selected from Tables Ia and Ib, resulting in the identification of the combination agents listed in Table 3b.
The protocol for the screening method is provided below.
1. Make complete medium and stock solutions: DMEM containing 10% FBS, 1% penicillin/streptomycin, 0.4 mg/ml G418,
Tetramethylrhodamine, ethyl ester, perchlorate ("TMRE") 10OnM diluted in complete media (above), and Carbonylcyanide-4-(trifluoromethoxy)-phenylhydrazone
("FCCP") stock: 50 μM in DMSO;
2. Warm up medium and 0.25% trypsin-EDTA to 33°C in water bath;
3. Aspirate old medium and wash once with PBS;
4. Add 7 ml 0.25% trypsin-EDTA to T 175 flask and sit for 5-6 minutes, rocking gently;
5. Incubate 2-3 minutes to be sure all cells are dissociated;
6. Add 8 mL of the medium to the flask to inactivate trypsin;
7. Pipette cells several times to make sure that cells are well separated;
8. Spin down 1000 rpm for five minutes; 9. Re-suspend in 5ml/flask full media and pipette up and down several times;
10. Count cells using hemacytometer or cellometer;
11. Make up final cell solution at a density of 178,000 cells/mL and seed 45 μl (8,000) cells / well into 384-well plates; 12. Put plates in incubator for ~2hrs, try not to stack plates together,
13. Aspirate and add 50 μl TMRE (final 10OnM) to columns 1-23, and add plain complete media to column 24. Incubate plates in dark at room temperature for 30 minutes;
14. Aspirate and add 45 μl media, add 5 μl compounds stock, incubate RT in dark for one hour;
15. Add FCCP 15 minutes before read;
16. Using the autowash, wash with complete media 2 x 5 minutes; and
17. Read plates in Envision at Ex/Em: 530nm/590nm with bottom mirror. Other Embodiments
All publications, patents, and patent applications mentioned in the above specification are hereby incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.
Other embodiments are in the claims.
What is claimed is:

Claims

1. A composition comprising:
(a) a first agent selected from the agents of Tables Ia and Ib; and
(b) a second, different agent selected from the classes and agents of Tables Ia, Ib, and 2.
2. The composition of claim 1, wherein said first agent and said second agent are selected from a single row of Tables 3a and 3b.
3. The composition of claim 1 or claim 2, wherein said first agent and said second agent are present in amounts that, when administered to a patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder.
4. The composition of claim 1 or claim 2, further comprising one or more additional agents selected from Tables Ia and Ib.
5. The composition of claim 1 or claim 2, further comprising at least one agent selected from the classes and agents of Table 2.
6. The composition of claim 1, wherein said first agent or said second agent is selected from the group consisting of a tricyclic antidepressant, an ionophore antibiotic, a cannabinoid agonist, a channel blocker, an antihistamine, a selective serotonin reuptake inhibitor, an anticholinergic, a IKK-β inhibitor, and an estrogen modulator.
7. The composition of claim 1, wherein said second agent is an antiapoptotic selected from the group consisting of minocycline, troglitazone, pioglitazone, and taurosodeoxycholic acid.
8. The composition of claim 1, wherein said second agent is an antidepressant selected from the group consisting of fluoxetine, sertraline hydrochloride, and nortriptyline.
9. The composition of claim 1, wherein said second agent is an antioxidant selected from the group consisting of lipoic acid, melatonin, BN 8251, OPC-14117, and ascorbate.
10. The composition of claim 1, wherein said second agent is an antipsychotic or psychotropic selected from the group consisting of haloperidol, clozapine, chlorpromazine, and olanzapine.
11. The composition of claim 1 , wherein said second agent is a bioenergetic selected from the group consisting of Coenzyme QlO, creatine, and dichloroacetate.
12. The composition of claim 1, wherein said second agent is a COX inhibitor or NSAID selected from the group consisting of flurbiprofen, naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, tolmetin, rofecoxib, celecoxib, valdecoxib, and lumiracoxib.
13. The composition of claim 1, wherein said second agent is a dopamine antagonist selected from the group consisting of olanzapine, quetiapine, and tetrabenazine.
14. The composition of claim 1, wherein said second agent is a glutamate antagonist selected from the group consisting of riluzole, remacemide, amantadine, memantine, ifendprodil, and eliprodil.
15. The composition of claim 1, wherein said second agent is a histone deacetylase inhibitor or transcription regulator selected from the group consisting of sodium butyrate, phenylbutyrate, suberoylanilide hydroxamic acid, and mithramycin.
16. The composition of claim 1, wherein said second agent is a heat shock protein regulator selected from the group consisting of geldanamycin, celastrol, bimoclomol, and arimoclomol.
17. The composition of claim 1, wherein said second agent is the immune modulator Copolymer 1.
18. The composition of claim 1, wherein said second agent is a mood stabilizer selected from the group consisting of lithium, valproate, and carbamazepine.
19. The composition of claim 1, wherein said second agent is a neuroleptic selected from the group consisting of haloperidol, perphenazine, and reserpine.
20. The composition of claim 1, wherein said second agent is a protein aggregation inhibitor selected from the group consisting of cystamine and trehalose.
I l l
21. The composition of claim 1 , wherein said second agent is a tranquilizer selected from the group consisting of clonazepam, a benzodiazepine, paroxetine, venlafaxine, and a beta-blocker.
22. The composition of claim 1, wherein said second agent is a trophic or restorative selected from the group consisting of GDNF, BDNF, CNTF, and a fetal striatal cell.
23. The composition of claim 1, wherein said second agent is selected from the group consisting of a cannabinoid, BCTC, lithium, ethyl-EPA, a free fatty acid, rapamycin, KW6002, and botulinum toxin.
24. The composition of claim 1 or claim 2, further comprising at least one agent selected from the classes and agents of Table 2.
25. The composition of claim 3, wherein said neurodegenerative disorder is a polyglutamine expansion disorder.
26. The composition of claim 25, wherein said polyglutamine expansion disorder is Huntington's disease.
27. The composition of any one of claims 1-26, wherein said composition is formulated for oral administration.
28. The composition of any one of claims 1-26, wherein said composition is formulated for systemic administration.
29. The composition of any one of claims 1-26, wherein said composition is formulated for intracranial, intrathecal, or epidural administration.
30. A method for treating, preventing, or ameliorating a neurodegenerative disorder, said method comprising administering to a patient one or more agents selected from the agents of Table 1 a in an amount sufficient to treat, prevent, or ameliorate said neurodegenerative disorder.
31. A method for treating, preventing, or ameliorating a neurodegenerative disorder, said method comprising administering to a patient a first agent selected from the agents of Table Ib, and a second, different agent selected from the classes and agents of Table 2, in amounts sufficient to treat, prevent, or ameliorate said neurodegenerative disorder.
32. A method for treating, preventing, or ameliorating a neurodegenerative disorder, said method comprising administering to a patient at least two different agents selected independently from the agents of Tables Ia and Ib, wherein the first and second agents are administered simultaneously or within 28 days of each other, in amounts that together are sufficient to treat, prevent, or ameliorate said neurodegenerative disorder.
33. The method of claim 32, wherein said first and second agents are selected from a single row of Tables 3a and 3b.
34. The method of claim 32 or 33, wherein said first and second agents are administered within 14 days of each other.
35. The method of claim 34, wherein said first and second agents are administered within 7 days of each other.
36. The method of claim 35, wherein said first and second agents are administered within 24 hours of each other.
37. The method of any one of claims 30-36, wherein said neurodegenerative disorder is a polyglutamine expansion disorder.
38. The method of claim 37, wherein said polyglutamine expansion disorder is Huntington's disease.
39. The method of any one of claims 30-36, wherein said neurodegenerative disorder is selected from the group consisting of Alexander disease, Alper's disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt- Jakob disease, dentatorubropallidoluysian atrophy, fragile X syndrome, fragile XE mental retardation, Friedreich's ataxia, ischemia stroke, Kennedy's disease, Krabbe disease, Lewy body dementia, multiple sclerosis, multiple system atrophy, myotonic dystrophy, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, Refsum's disease, Sandhoff disease, Schilder's disease, spinal cord injury, spinal muscular atrophy, spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, spinocerebellar ataxia type 6, spinocerebellar ataxia type 7, spinocerebellar ataxia type 8, spinocerebellar ataxia type 12, spinocerebellar ataxia type 17, Steele-Richardson-Olszewski disease, and Tabes dorsalis.
40. The method of any one of claims 30-36, wherein said agent or agents reduce the rate of neuronal death in said patient relative to the rate of neuronal death in a control.
41. The method of any one of claims 30-32, wherein said first agent or agents are selected from the group consisting of a tricyclic antidepressant, an ionophore antibiotic, a cannabinoid agonist, a channel blocker, an antihistamine, a selective serotonin reuptake inhibitor, an anticholinergic, a IKK-β inhibitor, and an estrogen modulator.
42. The method of any one of claims 30-36, wherein said patient is a human.
43. The method of any one of claims 30-36, further comprising an additional therapeutic regimen.
44. The method of claim 43, wherein said additional therapeutic regimen comprises administering to said patient an additional therapeutic agent, wherein said agent or agents selected from Tables Ia and Ib and said additional therapeutic agent are present in amounts that, when administered to said patient, are sufficient to treat, prevent, or ameliorate a neurodegenerative disorder.
45. The method of claim 44, wherein said additional therapeutic agent is selected from the classes and agents of Table 2.
46. The method of claim 45, wherein said additional therapeutic agent is an antiapoptotic selected from the group consisting of minocycline, troglitazone, pioglitazone, and taurosodeoxycholic acid.
47. The method of claim 45, wherein said additional therapeutic agent is an antidepressant selected from the group consisting of fluoxetine, sertraline hydrochloride, and nortriptyline.
48. The method of claim 45, wherein said additional therapeutic agent is an antioxidant selected from the group consisting of lipoic acid, melatonin, BN 8251, OPC- 14117, and ascorbate.
49. The method of claim 45, wherein said additional therapeutic agent is an antipsychotic or psychotropic selected from the group consisting of haloperidol, clozapine, chlorpromazine, and olanzapine.
50. The method of claim 45, wherein said additional therapeutic agent is a bioenergetic selected from the group consisting of Coenzyme QlO, creatine, and dichloroacetate.
51. The method of claim 45, wherein said additional therapeutic agent is a COX inhibitor or NSAID selected from the group consisting of flurbiprofen, naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid, fenoprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, tolmetin, rofecoxib, celecoxib, valdecoxib, and lumiracoxib.
52. The method of claim 45, wherein said additional therapeutic agent is a dopamine antagonist selected from the group consisting of olanzapine, quetiapine, and tetrabenazine.
53. The method of claim 45, wherein said additional therapeutic agent is a glutamate antagonist selected from the group consisting of riluzole, remacemide, amantadine, memantine, ifendprodil, and eliprodil.
54. The method of claim 45, wherein said additional therapeutic agent is a histone deacetylase inhibitor or transcription regulator selected from the group consisting of sodium butyrate, phenylbutyrate, suberoylanilide hydroxamic acid, and mithramycin.
55. The method of claim 45, wherein said additional therapeutic agent is a heat shock protein regulator selected from the group consisting of geldanamycin, celastrol, bimoclomol, and arimoclomol.
56. The method of claim 45, wherein said additional therapeutic agent is the immune modulator Copolymer 1.
57. The method of claim 45, wherein said additional therapeutic agent is a mood stabilizer selected from the group consisting of lithium, valproate, and carbamazepine.
58. The method of claim 45, wherein said additional therapeutic agent is a neuroleptic selected from the group consisting of haloperidol, perphenazine, and reserpine.
59. The method of claim 45, wherein said additional therapeutic agent is a protein aggregation inhibitor selected from the group consisting of cystamine and trehalose.
60. The method of claim 45, wherein said additional therapeutic agent is a tranquilizer selected from the group consisting of clonazepam, a benzodiazepine, paroxetine, venlafaxine, and a beta-blocker.
61. The method of claim 45, wherein said additional therapeutic agent is a trophic or restorative selected from the group consisting of GDNF, BDNF, CNTF, and a fetal striatal cell.
62. The method of claim 45, wherein said additional therapeutic agent is selected from the group consisting of a cannabinoid, BCTC, lithium, ethyl- EPA, a free fatty acid, rapamycin, KW6002, and botulinum toxin.
63. The method of claim 44, wherein said agent or agents selected from Tables Ia and Ib and said additional therapeutic agent are administered within 14 days of each other.
64. The method of claim 63, wherein said agent or agents selected from Tables Ia and Ib and said additional therapeutic agent are administered within 7 days of each other.
65. The method of claim 64, wherein said agent or agents selected from Tables Ia and Ib and said additional therapeutic agent are administered within 24 hours of each other.
66. The method of any one of claims 30-65, wherein said agent or agents selected from Tables Ia and Ib or said additional therapeutic agent are administered orally.
67. The method of any one of claims 30-65, wherein said agent or agents selected from Tables Ia and Ib or said additional therapeutic agent are administered systemically.
68. The method of any one of claims 30-65, wherein said agent or agents selected from Tables Ia and Ib or said additional therapeutic agent are administered intracranially, intrathecally, or epidurally.
69. A kit comprising:
(i) an agent selected from the agents of Tables Ia and Ib; and (ii) instructions for administering said agent to a patient having or at risk of having a neurodegenerative disorder.
70. A kit comprising:
(i) a composition comprising two agents selected from the agents of Tables Ia and Ib; and
(ii) instructions for administering said composition to a patient having or at risk of having a neurodegenerative disorder.
71. A kit comprising:
(i) a first agent selected from the agents of Tables Ia and Ib; (ii) a second agent selected from the agents of Tables Ia and Ib; and (iii) instructions for administering said first and said second agents to a patient having or at risk of having a neurodegenerative disorder.
72. The kit of claim 70 or 71, wherein said agents are selected from a single row of Tables 3a and 3b.
73. A kit comprising:
(i) an agent selected from the agents of Tables Ia and Ib; and (ii) instructions for administering said agent with a second agent selected from the agents of Tables Ia and Ib to a patient having or at risk of having a neurodegenerative disorder, wherein said second agent is not the agent in (i).
74. A kit comprising:
(i) a composition comprising:
(a) a first agent selected from the agents of Tables Ia and Ib; and
(b) a second agent selected from the classes and agents of Table 2; and
(ii) instructions for administering said composition to a patient having or at risk of having a neurodegenerative disorder.
75. A kit comprising:
(i) a first agent selected from the agents of Tables Ia and Ib; (ii) a second agent selected from the classes and agents of Table 2; and (iii) instructions for administering said first and said second agents to a patient having or at risk of having a neurodegenerative disorder.
76. A kit comprising:
(i) an agent selected from the agents of Tables Ia and Ib; and (ii) instructions for administering said agent and a second agent to a patient having or at risk of having a neurodegenerative disorder, wherein said second agent is selected from the classes and agents of Table 2.
77. A kit comprising:
(i) an agent selected from the classes and agents of Table 2; and
(ii) instructions for administering said agent with an agent selected from the agents of Tables Ia and Ib to a patient having or at risk of having a neurodegenerative disorder.
78. A method of identifying a combination that may be useful for the treatment, prevention, or amelioration of a neurodegenerative disorder, said method comprising the steps of:
(a) providing cells comprising a gene encoding a polyglutamine repeat polypeptide, wherein said polypeptide comprises an expanded polyglutamine repeat region relative to a wild-type polyglutamine repeat polypeptide;
(b) inducing expression of said gene;
(c) contacting said cells with an agent selected from the agents of Tables Ia and Ib and a candidate compound; and
(d) determining whether the combination of said agent and said candidate compound reduces perinuclear staining by a polyQ antibody relative to cells contacted with said agent but not contacted with the candidate compound, wherein a reduction in perinuclear staining identifies the combination as a combination useful for the treatment, prevention, or amelioration of a neurodegenerative disorder.
79. The method of claim 78, wherein said polyglutamine repeat polypeptide comprising said expanded polyglutamine repeat region comprises Htt Ql l l.
80. The method of claim 78, wherein said perinuclear staining is measured using immunocytochemistry analysis.
81. The method of claim 78, wherein said polyQ antibody comprises a 1F8 antibody.
82. The method of claim 78, wherein said cells are mouse striatal cells.
83. The method of claim 82, wherein said mouse striatal cells are STHdhQl 11 cells.
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