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WO2009099553A2 - Utilisation d’inhibiteur de kinase pour le traitement de l’athérosclérose - Google Patents

Utilisation d’inhibiteur de kinase pour le traitement de l’athérosclérose Download PDF

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Publication number
WO2009099553A2
WO2009099553A2 PCT/US2009/000590 US2009000590W WO2009099553A2 WO 2009099553 A2 WO2009099553 A2 WO 2009099553A2 US 2009000590 W US2009000590 W US 2009000590W WO 2009099553 A2 WO2009099553 A2 WO 2009099553A2
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csf
atherosclerosis
mice
disease
administration
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PCT/US2009/000590
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WO2009099553A3 (fr
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Zory Shaposhnik
Aldons J. Lusis
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The Regents Of The University Of California
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Publication of WO2009099553A2 publication Critical patent/WO2009099553A2/fr
Publication of WO2009099553A3 publication Critical patent/WO2009099553A3/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • Embodiments of the present invention are directed to inhibiting macrophage-colony stimulating factor (M-CSF) cell signaling and, in particular, the diseases caused by such signaling, by inhibiting or otherwise interfering with the biological activity of the M-CSF receptor, the product of the proto-oncogene c-fms.
  • M-CSF macrophage-colony stimulating factor
  • Cardiovascular disease is a major health risk throughout the industrialized world.
  • Atherosclerosis the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principle cause of death in the United States.
  • Atherosclerosis is a complex disease involving many cell types and molecular factors.
  • the process in normal circumstances, is a protective response to insults to the endothelium and smooth muscle cells (SMCs) of the wall of the artery, consists of the formation of fibrofatty and fibrous lesions or plaques, preceded and accompanied by inflammation.
  • SMCs smooth muscle cells
  • the advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive inflammatory-fibroproliferative response to numerous different forms of insult. For example, shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.
  • the first observable event in the formation of an atherosclerotic plaque occurs when blood-borne monocytes adhere to the vascular endothelial layer and transmigrate through to the sub-endothelial space. Adjacent endothelial cells at the same time produce oxidized low density lipoproteins (LDL). These oxidized LDL's are then taken up in large amounts by the monocytes through scavenger receptors expressed on their surfaces. In contrast to the regulated pathway by which native LDL (nLDL) is taken up by nLDL specific receptors, the scavenger pathway of uptake is not regulated by the monocytes.
  • LDL low density lipoproteins
  • Atherosclerotic plaques can occlude arteries gradually, leading to ischemia. Often, this type of plaque growth occurs gradually over time with a compensatory remodeling of the vessel lumen to maintain adequate perfusion. A large percentage of plaques do not result in what would be considered a significant angiographically measureable occlusion. If such plaques contain a thin fibrous cap and prominent macrophage foam cell core, they are characterized as unstable and prone to rupture.
  • Plaque rupture via the activity of proteases produced by infiltrating inflammatory macrophages, endothelial/SMC cell apoptosis or hemodynamic events
  • a rapid thrombosis as the tissue factor and other pro- coagulation factors present in plaques contact the blood stream resulting in a heart attack (if occurring within the coronary arteries) or stroke.
  • the rupture of unstable plaques can occur with no prior warning or symptoms or can be preceded by unstable angina.
  • plaques can lead to vessel occlusion and ischemia (when the vessel can no longer compensate by expanding lumen diameter) or a seemingly modest plaque (in terms of the amount protruding into the lumen) can rupture and trigger a very rapid thrombotic event.
  • Ischemia is a condition characterized by a lack of oxygen supply in tissues of organs due to inadequate perfusion. Such inadequate perfusion can have number of natural causes, including atherosclerotic or restenotic lesions, anemia, or stroke, to name a few. Many medical interventions, such as the interruption of the flow of blood during bypass surgery, for example, also lead to ischemia. In addition to sometimes being caused by diseased cardiovascular tissue, ischemia may sometimes affect cardiovascular tissue, such as in ischemic heart disease. Ischemia may occur in any organ, however, that is suffering a lack of oxygen supply.
  • Atherosclerotic disease of epicardial coronary arteries.
  • atherosclerosis causes an absolute decrease in myocardial perfusion in the basal state or limits appropriate increases in perfusion when the demand for flow is augmented.
  • Coronary blood flow can also be limited by arterial thrombi, spasm, and, rarely, coronary emboli, as well as by ostial narrowing due to luetic aortitis.
  • Congenital abnormalities such as anomalous origin of the left anterior descending coronary artery from the pulmonary artery, may cause myocardial ischemia and infarction in infancy, but this cause is very rare in adults.
  • Myocardial ischemia can also occur if myocardial oxygen demands are abnormally increased, as in severe ventricular hypertrophy due to hypertension or aortic stenosis. The latter can be present with angina that is indistinguishable from that caused by coronary atherosclerosis.
  • two or more causes of ischemia will coexist, such as an increase in oxygen demand due to left ventricular hypertrophy and a reduction in oxygen supply secondary to coronary atherosclerosis.
  • Unstable angina is a particular manifestation of atherosclerosis where the methods of the invention would be particularly effective.
  • a patient with chest pain at rest is described as having unstable angina. This condition is very serious, and indicates that the patient has an unstable cornary plaque on the verge of rupture. Such a plaque is highly inflamed and can rupture due to the activity of macrophages within the lesion. Such a patient will be monitored closely, undergo angiography, very likely resulting in balloon angioplasty or even bypass surgery. Short of these highly invasive procedures, few therapeutic options exist for this disease.
  • M-CSF was first identified as a factor that stimulates monoctye/macrophage colonies in semi-solid bone marrow cultures. It regulates monocyte/macrophage survival, differentiation, proliferation, migration and anti-infective potential by activating a signaling cascade mediated by its receptor, the tyrosine kinase proto-oncogene c-fms. Inflammatory disorders which display elevated levels of M-CSF include arthritis, obesity, and atherosclerosis. The potential involvement of M-CSF in atherosclerosis was suggested by the observation that M-CSF is induced in endothelial cells by treatment with oxidized lipids and is expressed at high levels in atherosclerotic lesions. However, these data do not address whether the molecule has a causative effect in these diseases, and several significant issues remain unresolved as to the role of M-CSF in these diseases. Publications.
  • the present invention provides methods and compositions for the treatment of cardiovascular disease, including but not limited to, atherosclerosis, ischemia/reperfusion, hypertension, restenosis, and arterial inflammation, particularly atherosclerosis.
  • a small molecule inhibitor of cFMS is administered to a patient in a dose effective in reducing the clinical indicia of atherosclerosis.
  • the administration is oral.
  • the inhibitor inhibits the ligand mediated signal transduction pathway that results in macrophage migration, survival, differentiation and proliferation, and thus decreases macrophage-mediated inflammation within the artery wall, resulting in decreased atherosclerosis, a more stabile atherosclerotic plaque less prone to rupture, and decreased restenosis after coronary angioplasty procedures.
  • the inhibitor has the structure (GW2580, SPG- 1 ):
  • R 1 and R 2 are independently selected from H, from a protecting group, e.g. Boc; a cleavable moiety useful in prodrug formulation, including a cleavable oligopeptide, an ester linkage, a cleavable carbohydrate, and the like; and a polymeric carrier, e.g. PEG, PLGA, and the like.
  • R 3 is selected from CH 3 , and a polymeric carrier, e.g. PEG, PLGA, and the like.
  • the inhibitor is GW2580 or a prodrug derivative therefore.
  • Such derivatives may be ester derivatives, where the attached ester substituents include one or more amino or carboxylate groups.
  • FIG. 1 Histochemical analysis of macrophage content in M-CSF deficient mice. Secondary antibody alone (negative control) (A). Lesional macrophages in female M-CSF +/+ LDLR " ' " animals (B) and M-CSF + ' " LDLR " ' “ animals (C) were detected with a MOMA-2 antibody (red). (D) Aortic root atherosclerotic lesion area positive for macrophages was measured and expressed as a percentage of intimal thickening area in each respective section.). Lintima, M: media, (magnification 20Ox)
  • FIG. 19 Effect of an M-CSF deficiency on atherosclerotic lesions in the proximal aorta. Lesions in aortic root sections of M-CSF +/+ and +/" mice were quantitated by lipid staining (A) and after bone marrow transplantations (C). (B) Representative lesion sections stained with Movat Pentachrome show collagen in yellow, SMCs in red and proteoglycans in blue. The lesion data are presented as box plots. See Methods for a description of box plots. [20] Figure 3. Inflammatory gene expression is suppressed in atherosclerotic lesions of M- CSF deficient mice.
  • FIG. 5 Effect of the M-CSF receptor kinase inhibitor on atherosclerotic lesions in the proximal aorta and on plasma PON activity. Lesions in aortic root sections of LDLR -/- mice on a Western diet treated twice a day with 80mg/kg of the M-CSF receptor kinase inhibitor for 8 weeks were quantitated by lipid staining (A). The lesion data are presented as box plots. See Methods for a description of box plots. Relative plasma PON activity after the 8-week treatment was determined in (B).
  • FIG. 6 Aortic and hepatic inflammatory gene expression is suppressed in LDLR-/- mice treated with the M-CSF receptor kinase inhibitor GW2580.
  • the relative expression level of MMP-9, ICAM-1 , E-Selectin, CSF-1 R, SRA, and F4/80 was examined by quantitative PCR of aortic RNA from LDLR-/- mice on a Western diet treated with GW2580 (A).
  • Aortic uPAR expression was examined in (B) while hepatic F4/80, CSF-1 R, CSF-1 , VCAM-1 , IL-6, and IL-1 beta expression is shown in (C). Data are presented as means +/-SEM and 6 mice from each category were tested.
  • FIG. 7 Effect of an M-CSF deficiency on atherosclerotic lesions in the ascending and thoracic and abdominal aorta.
  • the ascending and thoracic aorta was removed and cleared of all connective tissue before being fixed and pinned out. Lipids were stained for with Oil red O (red). En face staining of the thoracic and abdominal aorta from such animals is shown in (A).
  • the lesion data are presented as box plots (B). Lesions in aortic root sections of M-CSF +/+ and +/- mice were quantitated by lipid staining (C).
  • FIG. 8 Histochemical analysis of cell proliferation within aortic root lesions of M- CSF deficient mice. Proliferating cells within lesions of female M-CSF +/+ LDLR-/- animals (B) and M-CSF +/- LDLR-/- animals (C) were detected with a Ki67 antibody (red). Nuclei are stained by DAPI (blue). Secondary antibody alone (negative control) in (A). Proliferating cell nuclei in each lesion were counted and normalized by the total number of nuclei in the lesion (D). l:intima, M: media, (magnification 20Ox)
  • FIG. 9 Determination of monocyte/macrophage migration in response to M-CSF.
  • Neutralizing antibodies to M-CSF were added to an artery wall coculture in which oxidized- LDL mediated monocyte migration was measured (A). See Methods for details. Thioglycolate elicited peritoneal cells, highly enriched in macrophages, were quantitated in M-CSF +/+ LDLR -/- and M-CSF +/- LDLR -/- mice (B).
  • a representative example of a leukocyte flow cytometric scattergram for the resident (CD115+/Ly6C-low) and inflammatory (CD115+/Ly6C- high) monocyte subset is shown in (C).
  • FIG. 10 Effect of the M-CSF receptor kinase inhibitor GW2580 on monocyte migration.
  • the M-CSF kinase inhibitor was added to an artery wall coculture in which oxidized-LDL mediated monocyte migration was measured in (A) or MCP-1 mediated monocyte migration was measured in (B).
  • the ability of HDL (HDL Exp.) from inhibitor treated mice or control mice (HDL Cont.) to block monocyte migration or LDL to promote migration were measured in (C). See Methods for details.
  • FIG. 11 Plasma cholesterol levels in LDLR-/- mice treated with the M-CSF receptor kinase inhibitor GW2580. Total cholesterol levels after 8 weeks of a Western diet were determined in LDLR -/- treated with the cFMS kinase inhibitor.
  • FIG. 12 Quantitation of apoptosis in the aortic root of M-CSF deficient mice. This is an enlargement of Figure 4. Apoptotic nuclei (green, indicated with arrows) were detected with a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay in M-CSF +/+ LDLR-/- lesions (A), M-CSF +/- LDLR-/- lesions (B). Apoptotic cells were within areas of macrophage infiltration (see black circles), hintima, M: media, (magnification 40Ox).
  • TUNEL terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling
  • Atheromatous refers to a disease of the arterial blood vessels that results in hardening or furring of the arteries caused by the formation of multiple atheromatous plaques within the arteries.
  • the atheromatous plaque includes nodular accumulation of a soft, flaky, yellowish material at the center of large plaques, composed of macrophages nearest the lumen of the artery, sometimes with underlying areas of cholesterol crystals, and possibly also calcification at the outer base of older/more advanced lesions.
  • the atheromatous plaques though compensated for by artery enlargement, eventually lead to plaque ruptures and stenosis (i.e., narrowing) of the artery and, therefore, an insufficient blood supply to the organ it feeds.
  • the compensating artery enlargement process is excessive, then a net aneurysm results.
  • the complications associated with atherosclerosis are chronic, slowly progressing and cumulative.
  • the rupture of a soft plaque causes the formation of a blood clot (e.g., thrombus) that will rapidly slow or stop blood flow, e.g. 5 minutes, leading to death of the tissues fed by the artery.
  • a common recognized scenario is coronary thrombosis of a coronary artery causing myocardial infarction (i.e., a heart attack).
  • Another common scenario in advanced disease is claudication from insufficient blood supply to the legs, typically due to a combination of both stenosis and aneurysmal segments narrowed with clots. Kidney, intestinal and other arteries are also typically involved.
  • subject refers to any mammal, including humans, bovines, ovines, porcines, canines and felines, in need of treatment. In certain embodiments, the patient is a human. In general, the methods of the invention are applicable to pediatric and adult patients.
  • concentration in blood refers to a concentration of an agent obtained in whole blood or in a fluid obtained from blood, such as plasma or serum.
  • variants or derivatives of GW2580 embraces compounds which differ from the structure of GW2580 but which have substantially the same activity as native GW2580.
  • treatment refers to inhibiting the progression of a disease or disorder, e.g., atherosclerosis, or delaying the onset of a disease or disorder, whether physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or condition, or a symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease or disorder and/or adverse affect attributable to the disease or disorder.
  • Treatment covers any treatment of a disease or disorder in a mammal, such as a human, and includes: decreasing the risk of death due to the disease; preventing the disease of disorder from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; inhibiting the disease or disorder, i.e., arresting its development (e.g., reducing the rate of disease progression); and relieving the disease, i.e., causing regression of the disease.
  • Therapeutic benefits of the present invention include, but are not necessarily limited to, reduction of risk of onset or severity of disease or conditions associated with atherosclerosis.
  • a "therapeutically effective amount” refers to that amount of the compound sufficient to treat or manage a disease or disorder.
  • a therapeutically effective amount may refer to the amount of a compound that provides a therapeutic benefit in the treatment or management of a disease or disorder.
  • a therapeutically effective amount with respect to a compound of the invention means that amount of compound alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of a disease or disorder.
  • the term can encompass an amount that improves overall therapy, reduces or avoids unwanted effects, or enhances the therapeutic efficacy of or synergies with another therapeutic agent.
  • a "pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human.
  • a “pharmaceutical composition” is sterile, and free of contaminants that are capable of eliciting an undesirable response within the subject (e.g., the compound(s) in the pharmaceutical composition is pharmaceutical grade).
  • Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, subcutaneous, intradermal, intratracheal and the like. In some embodiments the composition is suitable for administration by an oral route.
  • the phrase "pharmaceutically acceptable carrier” refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredient. Said carrier medium is essentially chemically inert and nontoxic. [39] As used herein, the phrase “pharmaceutically acceptable” means approved by a regulatory agency of the Federal government or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly for use in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such carriers can be sterile liquids, such as saline solutions in water, or oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • a saline solution is an example of a suitable carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the carrier if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • These pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin.
  • suitable pharmaceutical carriers are a variety of cationic polyamines and lipids, including, but not limited to N-(1(2,3-dioleyloxy)propyl)- N,N,N-trimethylammonium chloride (DOTMA) and diolesylphosphotidylethanolamine (DOPE).
  • DOTMA N-(1(2,3-dioleyloxy)propyl)- N,N,N-trimethylammonium chloride
  • DOPE diolesylphosphotidylethanolamine
  • Liposomes are suitable carriers for gene therapy uses of the invention.
  • Such pharmaceutical compositions should contain a therapeutically effective amount of the compound, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • pharmaceutically acceptable derivatives of a compound of the invention include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. [42] As used herein, the phrase “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable, essentially nontoxic, acids and bases, including inorganic and organic acids and bases.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • an "immediate release" formulation of GW2580 refers to a drug composition or mixture of drug compositions in which there is no carrier that regulates the bioavailability of the drug's active ingredient(s) to tissues at the site of drug administration in the patient's body. It will be understood that any component of the formulation that limits or impairs access of the drug's active ingredient(s) to tissues at the site of drug administration in the patient's body is a carrier that regulates the bioavailability of the active ingredient(s) so affected for purposes of the foregoing definition.
  • in combination can also refer to regimen involving administration of two or more compounds.
  • “In combination with” as used herein also refers to administration of two or more compounds which may be administered in the same or different formulations, by the same of different routes, and in the same or different dosage form type.
  • the present invention provides methods and compositions for treating a subject having atherosclerosis.
  • the invention provides a method comprising administering to a subject having atherosclerosis an effective amount of an inhibitor of CSF-1 , including the inhibitor GW2580 or a derivative thereof, wherein the administering is effective to treat atherosclerosis in the subject.
  • Subjects suitable for treatment with the methods disclosed herein include subjects that suffer from atherosclerosis, particularly those having or at risk of an atherosclerotic disease event, such as stroke, acute coronary syndrome including heart attack, heart disease including congestive heart failure, peripheral artery occlusive disease, and the like.
  • Atherosclerosis is characterized by the deposition of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries. Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • the term "atherosclerotic disease event” as used herein is intended to encompass disease events arising from complications associated with atherosclerosis, including but not limited to, coronary heart disease events, cerebrovascular events, an acute coronray syndrome, and intermittent claudication.
  • Atherosclerosis of the coronary arteries commonly causes coronary artery disease, myocardial infarction, coronary thrombosis, and angina pectoris.
  • Atherosclerosis of the arteries supplying the central nervous system frequently provokes strokes and transient cerebral ischemia.
  • atherosclerosis causes intermittent claudication and gangrene and can jeopardize limb viability.
  • Atherosclerosis of an artery of the splanchnic circulation can cause mesenteric ischemia.
  • Atherosclerosis can also affect the kidneys directly (e.g., renal artery stenosis).
  • Acute coronary syndrome represents a form of acute destabilization of atherosclerotic plaques often caused by plaque rupture that results in acute myocardial ischemia.
  • Acute myocardial ischemia is chest pain due to insufficient blood supply to the heart muscle that results from coronary artery disease (also called coronary heart disease).
  • Patients who have symptoms of acute coronary syndrome may or may not exhibit an ST elevation (also referred to as an ST displacement) by electrocardiogram (ECG or EKG), which is diagnostic of damage to the cardiac muscle or strain on the ventricles.
  • Acute coronary syndrome thus encompasses the spectrum of clinical conditions ranging from unstable angina to non-Q-wave myocardial infarction and Q-wave myocardial infarction.
  • the method of this invention particularly serves to slow new atherosclerotic lesion or plaque formation, and to slow progression, including stopping progression, of existing lesions or plaques, as well as to cause regression of existing lesions or plaques.
  • this intervention may accelerate healing of unstable or ruptured plaque.
  • the methods of the invention contemplate methods for slowing the progression, including stopping progression, of atherosclerosis, including slowing atherosclerotic plaque progression, comprising administering a therapeutically effective amount of GW2580 or a derivative thereof to a patient in need of such treatment.
  • This method also includes slowing progression, including stopping progression, of atherosclerotic plaques existing at the time the instant treatment is begun (i.e., "existing atherosclerotic plaques"), as well as halting or stopping formation of new atherosclerotic plaques in patients with atherosclerosis.
  • the methods disclosed herein also encompass methods for regression of atherosclerosis, including regression of atherosclerotic plaques existing at the time the instant treatment is begun, comprising administering a therapeutically effective amount of GW2580 or a derivative thereof to a patient in need of such treatment.
  • the methods disclosed herein also encompass methods for slowing atherosclerotic plaque progression and/or accelerating plaque healing so as to reduce the risk of atherosclerotic plaque rupture comprising administering a prophylactically effective amount of GW2580 or a derivative thereof to a patient in need of such treatment, e.g. acute syndrome associated with impending plaque rupture.
  • Rupture as used herein refers to rupture of an atherosclerotic plaque often at the site of a thin fibrous cap, which potentially leads to thrombus formation and an acute event.
  • a further aspect of this invention involves a method for preventing or reducing the risk of developing atherosclerosis, comprising administering a prophylactically effective amount of the compounds described herein to a patient in need of such treatment.
  • Subject suitable for treatment according to the methods of the invention include those who a medical practitioner has diagnosed as having one or more symptoms of atherosclerosis, and particularly those patients who have had or are at risk of an atherosclerotic disease event. Diagnosis may be done by any suitable means. Methods for diagnosing atherosclerosis by measuring systemic inflammatory markers are described, for example, in U.S. Pat. No. 6,040,147, hereby incorporated by reference. Diagnosis and monitoring may employ an electrocardiogram, chest X-ray, cardiac catheterization, ultrasound (for the measurement of vessel wall thickness), or measurement of blood levels of CPK, CPK- MB, myoglobin, troponin, homocysteine, or C-reactive protein.
  • a patient at risk of development of an atherosclerotic disease event may have been subjected to the same tests (electrocardiogram, chest X-ray, etc.) or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors (e.g., family history, hypertension, diabetes mellitus, high cholesterol levels, smoking, obesity, etc.).
  • risk factors e.g., family history, hypertension, diabetes mellitus, high cholesterol levels, smoking, obesity, etc.
  • Atherosclerosis does not produce symptoms until it narrows the interior of an artery by more than 70%. Symptoms depend on location of the narrowing or blockage, which can occur almost anywhere in the body. Symptoms occur because as atherosclerosis narrows an artery more and more, tissues supplied by the artery may not receive enough blood and oxygen. The first symptom of a narrowing artery may be pain or cramps at times when blood flow cannot keep up with the tissues' need for oxygen. Typically, symptoms develop gradually as the atheroma slowly narrows an artery. However, sometimes the first symptoms occur suddenly because the blockage occurs suddenly — for example, when a blood clot lodges in an artery narrowed by an atheroma, causing a heart attack or stroke.
  • an effective amount of GW2580 or a derivative thereof reduces the area of an atherosclerotic lesion in an individual by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or more than 50%, compared to the area of atherosclerotic lesion in an individual not treated with GW2580.
  • GW2580 suitable for administration includes the structure (GW2580, SPG-1 ):
  • R 1 and R 2 are independently selected from H, from a protecting group, e.g. Boc; a cleavable moiety useful in prodrug formulation, including a cleavable oligopeptide, an ester linkage, a cleavable carbohydrate, and the like; and a polymeric carrier, e.g. PEG, PLGA, and the like.
  • R 3 is selected from CH 3 , and a polymeric carrier, e.g. PEG, PLGA, and the like.
  • the inhibitor is GW2580 or a prodrug derivative therefore.
  • Such derivatives may be ester derivatives, where the attached ester substituents include one or more amino or carboxylate groups.
  • Selection of the therapeutically effective dose can be determined (e.g., via clinical trials) by a skilled artisan, such as a clinician or a physician, based upon the consideration of several factors which will be known to one of ordinary skill in the art. Such factors include, for example, the particular form of GW2580, and the compound's pharmacokinetic parameters such as bioavailability, metabolism, half-life, and the like, which is established during the development procedures typically employed in obtaining regulatory approval of a pharmaceutical compound.
  • the dose include the disease or condition to be treated, the benefit to be achieved in a subject, the subject's body mass, the subject's immune status, the route of administration, whether administration of the compound or combination therapeutic agent is acute or chronic, concomitant medications, and other factors known by the skilled artisan to affect the efficacy of administered pharmaceutical agents.
  • the total pharmaceutically effective amount of GW2580 administered orally per dose will be in the range of about 1 ⁇ g/kg/day to about 500 mg/kg/day, including about 10 ⁇ g/kg/day to about 200 mg/kg/day, such as, about 40 ⁇ g/kg/day to about 100 mg/kg/day, of subject body weight, although, this will be subject to a great deal of therapeutic discretion.
  • the GW2580 therapy of the invention may be administered to the patient in the form of a single or twice daily administration of an immediate release formulation of GW2580.
  • Administration of the pharmaceutical compositions of the invention includes, but is not limited to, oral, intravenous infusion, subcutaneous injection, intramuscular, topical, depo injection, implantation, time-release mode, intracavitary, intranasal, inhalation, intralesional, intraocular, immediate release, and controlled release.
  • the pharmaceutical compositions of the invention also may be introduced parenterally, transmucosally (e.g., orally), nasally, rectally, intravaginally, sublingually, submucosally, or transdermally.
  • administration is parenteral, i.e., not through the alimentary canal but rather through some other route via, for example, intravenous, subcutaneous, intramuscular, intraperitoneal, intraorbital, intracapsular, intraspinal, intrastemal, intra-arterial, or intradermal administration.
  • the administering of GW2580 is by other than direct administration to the pericardial space.
  • the administering of GW2580 is by systemic administration.
  • GW2580 is systemically administered by subcutaneous bolus injection.
  • the present invention further provides methods for treating a subject having atherosclerosis using a pharmaceutical composition of GW2580 or derivative thereof, and a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include essentially chemically inert and nontoxic pharmaceutical compositions that do not interfere with the effectiveness of the biological activity of the pharmaceutical composition.
  • suitable pharmaceutical carriers include, but are not limited to, saline solutions, glycerol solutions, ethanol, N-(1(2,3-dioleyloxy)propyl)- N,N,N-trimethylammonium chloride (DOTMA), diolesylphosphotidylethanolamine (DOPE), and liposomes.
  • DOTMA N-(1(2,3-dioleyloxy)propyl)- N,N,N-trimethylammonium chloride
  • DOPE diolesylphosphotidylethanolamine
  • liposomes Such pharmaceutical compositions should contain a therapeutically effective amount of the compound, together with a suitable amount of carrier so as to provide the
  • compositions of the invention can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • compositions adapted for oral administration may be provided, for example, as capsules or tablets; as powders or granules; as solutions, syrups or suspensions (in aqueous or non-aqueous liquids); as edible foams or whips; or as emulsions.
  • Tablets or hard gelatine capsules may comprise, for example, lactose, starch or derivatives thereof, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, stearic acid or salts thereof.
  • Soft gelatine capsules may comprise, for example, vegetable oils, waxes, fats, semi-solid, or liquid polyols, etc.
  • Solutions and syrups may comprise, for example, water, polyols and sugars.
  • An active agent intended for oral administration may be coated with or admixed with a material (e.g., glyceryl monostearate or glyceryl distearate) that delays disintegration or affects absorption of the active agent in the gastrointestinal tract.
  • a material e.g., glyceryl monostearate or glyceryl distearate
  • the sustained release of an active agent may be achieved over many hours and, if necessary, the active agent can be protected from being degraded within the gastrointestinal tract.
  • pharmaceutical compositions for oral administration may be formulated to facilitate release of an active agent at a particular gastrointestinal location.
  • GW2580 may be administered using long-acting GW2580 formulations that either delay the clearance of GW2580 from the site or cause a slow release of GW2580 from, e.g., an injection or administration site.
  • the long-acting formulation that prolongs GW2580 plasma clearance may be in the form of GW2580 complexed, or covalently conjugated (by reversible or irreversible bonding) to a macromolecule such as a water-soluble polymer selected from PEG and polypropylene glycol homopolymers and polyoxyethylene polyols, i.e., those that are soluble in water at room temperature. See, e.g., U.S. Patent No.
  • the GW2580 may be complexed or bound to a polymer to increase its circulatory half-life.
  • polyethylene polyols and polyoxyethylene polyols useful for this purpose include polyoxyethylene glycerol, polyethylene glycol, polyoxyethylene sorbitol, polyoxyethylene glucose, or the like.
  • the glycerol backbone of polyoxyethylene glycerol is the same backbone occurring in, for example, animals and humans in mono-, di-, and triglycerides.
  • the polymer need not have any particular molecular weight. In some embodiments, the molecular weight is between about 3500 and 100,000, or between 5000 and 40,000.
  • the PEG homopolymer is unsubstituted, but it may also be substituted at one end with an alkyl group.
  • An exemplary alkyl group is a C1-C4 alkyl group, e.g., a methyl group.
  • the polymer is an unsubstituted homopolymer of PEG, a monomethyl- substituted homopolymer of PEG (mPEG), or polyoxyethylene glycerol (POG) and has a molecular weight of about 5000 to 40,000.
  • the GW2580 regimen of the invention can be modified to include the use of additional agents for treating atherosclerosis or an atherosclerotic disease event, e.g., stroke, heart attack, heart disease including congestive heart failure, peripheral artery occlusive disease, and the like.
  • additional agents for treating atherosclerosis or an atherosclerotic disease event e.g., stroke, heart attack, heart disease including congestive heart failure, peripheral artery occlusive disease, and the like.
  • One or more additional active agents may be used in combination with the GW2580 therapy of this invention in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration of the active agents.
  • the additional active agent or agents can be lipid altering compounds such as HMG-CoA reductase inhibitors, or agents having other pharmaceutical activities, or agents that have both lipid-altering effects and other pharmaceutical activities.
  • HMG-CoA reductase inhibitors useful for this purpose include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (see U.S. Pat. No.
  • ALTOPREVTM simvastatin
  • simvastatin see U.S. Pat. No. 4,444,784
  • ZOCORTM dihydroxy open-acid simvastatin, particularly the ammonium or calcium salts thereof
  • pravastatin PRAVACHOLTM
  • LESCOLTM fluvastatin
  • LIPITORTM atorvastatin
  • nisvastatin PITAVATM
  • NK-104 also referred to as PCT international publication number WO 97/23200
  • CRESTORTM also known as ZD4522, see U.S. Pat. No. 5,260,440
  • Additional active agents which may be employed in combination with GW2580 include but are not limited to 5-lipoxygenase inhibitors, HMG-CoA synthase inhibitors; cholesterol ester transfer protein (CETP) inhibitors, for example JTT-705 and CP529.414; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors including selective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors of ACAT1 and -2; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein llb/llla fibrinogen receptor antagonists and aspirin; human peroxisome proliferator
  • Cholesterol absorption inhibitors can also be used in combination with GW2580 of the present invention. Such compounds block the movement of cholesterol from the intestinal lumen into enterocytes of the small intestinal wall, thus reducing serum cholesterol levels. Examples of cholesterol absorption inhibitors are described in U.S. Pat. Nos. 5,846,966, 5,631 ,365, 5,767,115, 6,133,001 , 5,886,171 , 5,856,473, 5,756,470, 5,739,321 , 5,919,672, and in PCT application Nos.
  • the most notable cholesterol absorption inhibitor is ezetimibe (ZETIATM), also known as 1-(4-fluorophenyl)-3(R)- [3(S)-(4-fl- uorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, described in U.S. Pat. Nos. 5,767,115 and 5,846,966.
  • GW2580 may also be administered in conjunction with one or more additional agents such as anti-inflammatory agents (e.g., non-steroidal anti-inflammatory drugs (NSAIDs; e.g., detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, aspirin, choline salicylate, salsalte, and sodium and magnesium salicylate) and steroids (e.g., cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone)),
  • Surgical treatment is also envisioned as a combination therapy in conjunction with administration of GW2580.
  • balloon angioplasty can open up narrowed vessels and promote an unproved blood supply.
  • a metallic stenting element can be inserted and used to permanently maintain the walls of the vessel treated in its extended opened state.
  • Vascular stents are small mesh tubes made of stainless steel or other metals and are used to prop open the weak inner walls of atherosclerotic arteries. They are often used in conjunction with balloon angioplasty to prevent restenosis after the clogged arteries are treated.
  • the blood supply to the heart muscle can also be restored through a vein graft bypass.
  • These secondary therapeutic agents may be administered within 14 days, 7 days, 1 day, 12 hours, or 1 hour of administration of GW2580, or simultaneously therewith.
  • the additional therapeutic agents may be present in the same or different pharmaceutical compositions as GW2580.
  • different routes of administration may be used. For example, a second agent may be administered orally, while GW2580 may be administered by intravenous, intramuscular, or subcutaneous injection.
  • Kits with unit doses of the subject compounds, usually in oral or injectable doses, are provided.
  • kits in addition to the containers containing the unit doses will be an informational package insert describing the use and attendant benefits of the GW2580 in treating atherosclerosis.
  • human LDL was incubated with a human endothelial cell/smooth muscle cell coculture. This LDL induces the production of factors, including M-CSF and MCP-1 , that mediate monocyte migration. Subsequently, labeled human monocytes were added to the culture in addition to various doses of GW2580. The monocytes were and allowed to migrate into the coculture. Migrated monocytes were then quantitated microscopically. Human- derived HDL (which inhibits the production of M-CSF and MCP-1 ) and the DMSO carrier were used as positive and negative controls in this experiment. We also tested the ability of GW2580 to decrease monocyte migration in response to direct MCP-1 addition to the culture media. In both cases, GW2580 (in a dose dependant manner) was able to decrease monocyte migration as well as the control HDL.
  • M-CSF pharmacological inhibition of M-CSF
  • IAM-1 adhesion factors
  • F4/80 macrophage markers
  • II-6, 11-1 beta inflammatory cytokines
  • MMP-9 macrophage matrix degradation enzymes
  • GW2580 can suppress inflammatory aspects of early, intermediate and advanced atherosclerotic lesions.
  • Vascular cell-derived M-CSF is primarily responsible for lesion formation and mechanisms for M-CSF's effect on atherosclerosis include monocyte recruitment and macrophage survival.
  • GW2580 suppresses inflammation and lesion formation by inhibiting M-CSF signaling within the artery wall.
  • mice After 10 generations of backcrossing, we intercrossed heterozygous mice. Over 120 mice from this cross were genotyped, resulting in a ratio that was greatly skewed from the expected 1 :2:1 ratio, such that approximately equal numbers of +/+ and +/" mice were observed and only two of the mice were of the " ' " genotype. Thus, both the heterozygous and homozygous null genotypes were associated with dramatically reduced viability. Even on a mixed genetic background, M-CSF " ' " mice had reduced size and weight at birth as well as osteopetrosis and a lack of tooth eruption. Therefore, we chose to use primarily heterozygous mice in this study. Both male and female mice were examined. [88] Atherosclerotic Lesions.
  • mice This decrease was not observed in the thoracic and abdominal aorta of female M-CSF + ' " mice, as measured by en face staining of lipids (Fig. 7).
  • mice We also examined other characteristics of those mice and observed no differences in plasma lipids, circulating monocytes (Table I), overall number of cells per unit of lesion area or in the number of proliferating cells (Figure 8), fibrous caps or prominent lipid cores per aortic root section (Table II).
  • M-CSF Derived from Monocyte/Macrophages does not Influence Lesion Development. As discussed above, monocytes/macrophages are capable of abundant M-CSF expression.
  • bone marrow transplantation experiments We transplanted bone marrow from M-CSF +/+ , +/" and " ' " donors into lethally irradiated LDLR " ' " recipients and placed the animals on a 12 week Western diet. No significant differences were detected in aortic root atherosclerosis ( Figure 2), plasma M-CSF levels or circulating monocyte counts (Table II) between animals receiving M-CSF +/+ , +/' or " ' " bone marrow.
  • Plasma M-CSF levels are a combination of values from male and female M-CSF +/- LDLR -/- recipients
  • Female M-CSF + ' ' lesion sections did not show an increase in apoptotic cell content relative to lesion.
  • ICAM-1 and E-Selectin both factors expressed by the endothelium early in plaque formation and involved in the firm adhesion of monocytes to the artery wall prior to their entry showed 70% to 80% reduced expression in the M-CSF receptor inhibitor treated group.
  • Urokinase plasminogen activator receptor (uPAR) a direct target of M-CSF signaling was significantly down-regulated as well (Fig. 6B).
  • F4/80 levels declined 50% (Fig.
  • M-CSF expression was substantially decreased in M- CSF + ' " mice, but by far more than 50% that would be expected from the decreased female MOMA-2 staining. Macrophages themselves can express M-CSF and a significant decrease in macrophage content was noted in M-CSF +/" lesions. Also, decreased expression of SR-A, a macrophage scavenger receptor up regulated in response to M-CSF, was noted.
  • M-CSF + ' " LDLR " ' " animals have significantly fewer thioglycolate elicited peritoneal cells, a population of cells rich in macrophages, suggesting an in vivo role for M-CSF in macrophage migration.
  • CD115(M-CSF receptor) and Ly6C have been used to define two different populations of monocytes.
  • CD115+/Ly6C-high expressing cells represent monocytes that are prone to migrate to sites of inflammation, including atherosclerotic lesions.
  • CD115+/Ly6C-low monocytes tend to become resident tissue macrophages rather than migrating in response to inflammatory stimuli.
  • GW2580 a compound that has demonstrated to have at least 100-fold greater inhibitory capacity for the M-CSF receptor kinase relative to an array of related kinases such as the PDGF and VEGF receptor tyrosine kinases.
  • GW2580 was administered at a dose required to maintain free plasma levels (unbound to albumin) of the inhibitor in the range of 100 nM, near the IC 50 for inhibiting monocyte growth with the assumption that albumin associated compound having very limited bioactivity.
  • GW2580 suppressed atherogenesis to about the same extent observed in M-CSF heterozygous mice ( Figure 2A).
  • kinase inhibitors including imatinib and SU11248 can inhibit M-CSF receptor kinase activity, they also inhibit several other kinases and are in no way selective for that target.
  • M-CSF heterozygous mice on a C57BL/6JxC3HeB/FeJ mixed genetic background were purchased from the Jackson Laboratory and backcrossed for ten generations to C57BL/6J mice.
  • M-CSF heterozygous mice on an inbred genetic background were then crossed to LDLR " ' " mice on a C57BL/6J background to produce double heterozygous mice that were again crossed to LDLR " ' ' mice.
  • M-CSF + ' ' LDLR " ' " mice were selected and intercrossed to produce M-CSF +/+ , +/" and " ' " mice on an LDLR null background.
  • M-CSF " ' " mice In order to produce M-CSF " ' " mice as donors for bone marrow transplantation, we transferred the M-CSF null mutation onto a mixed genetic background that still maintained a b H2 haplotype, allowing tissue transplant compatibility with the C57BL/6J strain. M-CSF + ' " animals on the C57BL/6J background were crossed to the inbred 129T2/SvEMsJ strain (Jackson Laboratory) to create mice that preserved the b H2 haplotype on a mixed genetic background. M-CSF + ' " animals were selected and intercrossed to produce M-CSF +/+ , M-CSF + ' " and M-CSF " ' " animals on the mixed background.
  • M-CSF +/+ and M-CSF + ' " animals were maintained on a chow diet but M-CSF " ' " , which lack teeth, were maintained on a powdered chow diet.
  • the region containing the single base pair insertion creating the M-CSF null allele was amplified by fluorescent PCR using the following primers: 5'-CGC ATG GTC TCA TCT ATT ATG TCT TG-3' and 5'-CTG CTC CTC ATA GTC CTT GG-3'.
  • the products (153 bp for the normal allele and 154 bp for the mutant allele) were resolved on an ABI Genotyper.
  • GW2580 was synthesized as previously described. Purity was greater than 98.6% as determined by HPLC analysis. Further characterization and validation of the compound structure was done by NMR and mass spectrometry as well as elemental analysis to rule out contaminating elements. GW2580 was added to a carrier solution of 0.5% hydroxymethycellulose/0.1 % Tween 20 prior to oral administration of 80mg/kg twice a day for 8 weeks to 8-week-old LDLR " ' " female mice purchased from the Jackson Laboratory.
  • Plasma Lipid, Glucose, and M-CSF Levels Animals were fasted overnight before being bled from the retroorbital sinus. Plasma was collected and used to determine total cholesterol and HDL cholesterol levels. Plasma paraoxonase activity and lipids were determined as described previously. Plasma glucose was determined in triplicate using a commercial kit (#315-100; Sigma). Plasma collected at time of sacrifice was used to measure circulating levels of M-CSF by ELISA (R&D Systems).
  • Sections were stained with oil red O and hematoxylin, counterstained with fast green, and lesion areas quantitated by light microscopy. Additionally, the ascending and descending aorta (to the diaphragm) was dissected, cleaned of connective tissue and fixed. The aortas were then pinned out en face and stained with Oil red O as in Tangirala et al. Lesion surface area and total aortic surface area were measured using Image Pro Plus (Media Cybernetics).
  • Staining was detected using the Alkaline Phosphatase Standard ABC Kit (Vector Labs) and Vector Red as a substrate that fluoresces in a spectrum similar to Rhodamine. Sections were counterstained with DAPI and imaged on a Zeiss Axioskop 2 florescent microscope. Omission of the primary antibody was included as one control to determine staining specificity.
  • Pre-immune serum an irrelevant antibody and anti-granulocyte colony stimulating factor (G-CSF) antibodies, were used as negative controls.
  • G-CSF granulocyte colony stimulating factor
  • Apoptosis Quantitation The ApopTag Fluorescein In Situ Apoptosis Detection Kit (Chemicon), utilizing a terminal deoxynucleotidyl transferase (TdT) based technique, was used to quantitate apoptosis within atherosclerotic lesions of the aortic root. Five to six 5 ⁇ m cryosections sections from six to eight animals of each genotype and sex were selected and dried overnight at room temperature before using the assay. Lesions were examined at 20Ox magnification for apoptotic nuclei and over 150 TUNEL+ nuclei for each genotype were detected. Positive nuclei were confirmed by colocalization with nuclear DAPI staining at 40Ox magnification.
  • GW2580 can also be formulated in a combination with lactic and glycolic acid (PLGA) to provide microspheres with improved solubility and sustained drug release.
  • PLGA lactic and glycolic acid
  • GW2580 is conjugated to improve pharmacodynamic properties. A synthetic scheme to conjugate monomethoxy-polyethylene glycol-polylactic acid is shown below:
  • GW2580 can also be modified by conjugation of an esterase, protease, phosphatase cleavable moiety to the drug, e.g. as shown below, where R is an ester, cleavable oligopeptide, cleavable polysaccharide, and the like.
  • R is an ester, cleavable oligopeptide, cleavable polysaccharide, and the like.
  • the compound is activated to the active compound by cleavage of the group.

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Abstract

La présente invention concerne des méthodes et des compositions destinées au traitement d’une maladie cardiovasculaire. Selon les méthodes de l'invention, un inhibiteur à petites molécules de cFMS est administré à un patient en une dose efficace pour réduire les signes cliniques d’athérosclérose.
PCT/US2009/000590 2008-02-01 2009-01-30 Utilisation d’inhibiteur de kinase pour le traitement de l’athérosclérose WO2009099553A2 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104529911A (zh) * 2014-12-31 2015-04-22 华中农业大学 一种氚标记艾地普林的制备方法
WO2018093591A1 (fr) 2016-11-03 2018-05-24 Juno Therapeutics, Inc. Polythérapie de thérapie cellulaire et d'inhibiteur de la microglie
WO2018223098A1 (fr) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles de fabrication et procédés liés à la toxicité associée à la thérapie cellulaire
WO2018223101A1 (fr) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles de fabrication et procédés de traitement utilisant une thérapie cellulaire adoptive
WO2019006427A1 (fr) 2017-06-29 2019-01-03 Juno Therapeutics, Inc. Modèle murin pour évaluer des toxicités associées à des immunothérapies
WO2019046832A1 (fr) 2017-09-01 2019-03-07 Juno Therapeutics, Inc. Expression génique et évaluation d'un risque de développement d'une toxicité suite à une thérapie cellulaire
WO2019089848A1 (fr) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Procédés associés à une charge tumorale pour évaluer une réponse à une thérapie cellulaire
WO2020113194A2 (fr) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Méthodes pour le traitement par thérapie cellulaire adoptive
WO2020113188A2 (fr) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Méthodes de dosage et de traitement de malignités de lymphocytes b au moyen d'une thérapie cellulaire adoptive
WO2021113770A1 (fr) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Procédés liés à la toxicité et à la réponse associées à une thérapie cellulaire pour le traitement de tumeurs malignes des lymphocytes b

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070060577A1 (en) * 2005-09-14 2007-03-15 Player Mark R 5-Oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of c-fms kinase
US7247618B2 (en) * 2001-04-30 2007-07-24 Tripathi Rajavashisth Methods for inhibiting macrophage colony stimulating factor and c-FMS-dependent cell signaling

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7247618B2 (en) * 2001-04-30 2007-07-24 Tripathi Rajavashisth Methods for inhibiting macrophage colony stimulating factor and c-FMS-dependent cell signaling
US20070060577A1 (en) * 2005-09-14 2007-03-15 Player Mark R 5-Oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of c-fms kinase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CONWAY ET AL.: 'Inhibition of colony-stimulating-factor-1 signaling in vivo with the orally bioavailable cFMS kinase inhibitor GW2580.' PNAS vol. 102, November 2005, pages 16078 - 16083 *

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CN104529911A (zh) * 2014-12-31 2015-04-22 华中农业大学 一种氚标记艾地普林的制备方法
WO2018093591A1 (fr) 2016-11-03 2018-05-24 Juno Therapeutics, Inc. Polythérapie de thérapie cellulaire et d'inhibiteur de la microglie
US11413310B2 (en) 2017-06-02 2022-08-16 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
WO2018223098A1 (fr) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles de fabrication et procédés liés à la toxicité associée à la thérapie cellulaire
WO2018223101A1 (fr) 2017-06-02 2018-12-06 Juno Therapeutics, Inc. Articles de fabrication et procédés de traitement utilisant une thérapie cellulaire adoptive
US11944647B2 (en) 2017-06-02 2024-04-02 Juno Therapeutics, Inc. Articles of manufacture and methods for treatment using adoptive cell therapy
US11740231B2 (en) 2017-06-02 2023-08-29 Juno Therapeutics, Inc. Articles of manufacture and methods related to toxicity associated with cell therapy
WO2019006427A1 (fr) 2017-06-29 2019-01-03 Juno Therapeutics, Inc. Modèle murin pour évaluer des toxicités associées à des immunothérapies
WO2019046832A1 (fr) 2017-09-01 2019-03-07 Juno Therapeutics, Inc. Expression génique et évaluation d'un risque de développement d'une toxicité suite à une thérapie cellulaire
WO2019089848A1 (fr) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Procédés associés à une charge tumorale pour évaluer une réponse à une thérapie cellulaire
WO2020113188A2 (fr) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Méthodes de dosage et de traitement de malignités de lymphocytes b au moyen d'une thérapie cellulaire adoptive
WO2020113194A2 (fr) 2018-11-30 2020-06-04 Juno Therapeutics, Inc. Méthodes pour le traitement par thérapie cellulaire adoptive
EP4393547A2 (fr) 2018-11-30 2024-07-03 Juno Therapeutics, Inc. Procédés de dosage et de traitement de tumeurs malignes de lymphocytes b dans une thérapie cellulaire adoptive
EP4427810A2 (fr) 2018-11-30 2024-09-11 Juno Therapeutics, Inc. Procédés de traitement utilisant une thérapie cellulaire adoptive
WO2021113770A1 (fr) 2019-12-06 2021-06-10 Juno Therapeutics, Inc. Procédés liés à la toxicité et à la réponse associées à une thérapie cellulaire pour le traitement de tumeurs malignes des lymphocytes b

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