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WO1993017701A1 - Peptides se liant au recepteur d'endotheline - Google Patents

Peptides se liant au recepteur d'endotheline Download PDF

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Publication number
WO1993017701A1
WO1993017701A1 PCT/US1993/002195 US9302195W WO9317701A1 WO 1993017701 A1 WO1993017701 A1 WO 1993017701A1 US 9302195 W US9302195 W US 9302195W WO 9317701 A1 WO9317701 A1 WO 9317701A1
Authority
WO
WIPO (PCT)
Prior art keywords
side chain
leu
asp
val
inclusive
Prior art date
Application number
PCT/US1993/002195
Other languages
English (en)
Inventor
David H. Coy
Simon J. Hocart
Wojciech J. Rossowski
Original Assignee
The Administrators Of The Tulane Educational Fund
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Administrators Of The Tulane Educational Fund filed Critical The Administrators Of The Tulane Educational Fund
Priority to AU38021/93A priority Critical patent/AU3802193A/en
Publication of WO1993017701A1 publication Critical patent/WO1993017701A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Endothelin is a potent vasoconstrictor peptide of the following formula (see Yanagisawa M. , et al. Nature 332:411 [1988]) :
  • endothelin As an endogenous peptide, endothelin, by controlling liberation of various substances, directly or indirectly induces sustained contraction of vascular or non-vascular smooth muscles.
  • endothelin serves as an important mediator involved in diseases such as endotoxin shock, endotoxin-induced renal failure or hypertension.
  • an objective of the present invention relates to therapeutics for the treatment of the above- mentioned various diseases by providing potent endothelin receptor-binding peptides.
  • the present invention features a series of novel cyclic pentapeptides of the formula: cyclo (D-Trp-D-Asp-X-D-Val-Leu) (I) or pharmaceutically acceptable salts thereof.
  • X is an «-amino acid with a conformationally restricted side chain and the side chain contains 4-16 carbons, comprisi e.
  • Trp, Asp, X or the like herein stands for an a ino acid residue, -NH-CH(R)-CO-, where R denotes the side chain (or identifying group) of an amino acid or its residue, e.g., R is -CH 2 COOH for Asp.
  • the amino acid residue is optically active, it is the L- form configuration that is intended unless D-form is expressly designated.
  • N-terminus is at the left and the C- terminus at the right in accordance with the conventional representation of a polypeptide chain.
  • a short line between two amino acid residues indicates a peptide bond.
  • the prefix "cyclo" indicates the presence of a peptide bond between the N-terminus and C-terminus.
  • a cyclic peptide herein refers to a peptide chain with such a structural feature.
  • a conformationally restricted side chain herein is a side chain which is less flexible and cannot rotate as freely as that of a natural amino acid (except Pro or hydroxy-Pro) .
  • Such conformational constraint can be achieved either by tethering the side chain to the NH group of the peptide bond to form a ring structure or ring structures, thus preventing rotating and bending of the side group.
  • the flexibility of a side chain can be lowered as a result of steric hindrance.
  • Pharmaceutically acceptable salts of the peptides of the invention include, but are limited to, sodium salt, potassium salt and ammonium salt.
  • Preferred embodiments of the invention are the cyclic pentapeptides of formula (I) , in which the side chain and C ⁇ and if of X form 1-3, inclusive, separate or fused rings with the ⁇ and ⁇ f ⁇ being members of one of the rings or pharmaceutically acceptable salts thereof.
  • Particularly preferred pentapeptides of the invention are those in which the rings are fused; for example, X is a D- or L- isomer of Tec, Tip, Oic, or Tic (see below for full names and structures) .
  • the invention also includes cyclic pentapeptides of the formula: cyclo (D-Trp-D-X-Y-D-Val-Leu) (II) or pharmaceutically acceptable salts thereof.
  • X is Ser or Thr and Y is an ⁇ -amino acid with a conformationally restricted side chain.
  • the side chain and * and N* of Y in formula (II) form 1-3, inclusive, separate or fused rings with the C" and N* being members of one of the rings.
  • Y can be a D- or L- isomer of Pro, hydroxy-Pro, Tec, Tip, Oic, or Tic.
  • Hydroxy-Pro herein refers to any of 2-hydroxy-Pro, 3-hydroxy-Pro, 4-hydroxy-Pro, and 5- hydroxy-Pro; 4-hydroxy-Pro is preferred.
  • Also included in the present invention is a solid- phase chemical synthetic method for preparing a cyclic pentapeptide having the formula of cyclo (D-Trp-D-Asp-X- D-Val-Leu) , wherein X is an «-amino acid with a conformationally restricted side chain, the side chain containing 4-16 carbons, inclusive, which synthetic method comprises the steps of:
  • the side chain and ( and i of X may form 1-3, inclusive, separate or fused rings with the * and i being members of one of the rings.
  • X can be a D- or L-isomer of Tec, Tip, Oic, or Tic.
  • Another synthetic method of the invention is an improvement in preparing a cyclic peptide from a linear peptide of 3-10 amino acid residues, inclusive, with an N-terminal residue or a residue adjacent thereto having a carboxyl group-containing side chain by forming a peptide bond between the «*-amino group of the ⁇ -terminal residue and the «-carboxyl group of the C-terminal residue of the linear peptide, the improvement being forming the peptide bond with the carboxyl group unprotected.
  • cyclic pentapeptides which can be prepared by this improved method are cyclo (D-Trp-D-Asp-Tic-D-Val-Leu) cyclo (D- Trp-D-Asp-Tic-D-Val-Leu) , cyclo (D-Trp-D-Asp-Tip-D-Val- Leu) .
  • the N-terminal residue is Asp and the linear peptide may contain 3-7, or preferably 4-6 amino acid residues, inclusive.
  • the ⁇ -terminal residue does not have a carboxyl-group containing side chain and the residue adjacent to the ⁇ -terminal residue has a carboxyl-group containing side chain, such as CH 2 -COOH or CH 2 -CH 2 -COOH.
  • the method can be used to link the C- and N-termini of a linear peptide which either (1) has an Asp side chain in its N terminal residue, the residue adjacent thereto, or both, or (2) has a Glu side chain only in the position adjacent to the N-terminus, but not in the N-terminus.
  • a further aspect of the invention is a method of treating hypertension, nephritis, acute renal failure, cyclosporin-induced renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, asthma, atherosclerosis, cardiac graft rejection, restenosis, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation in a mammalian subject, which method includes administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a cyclic pentapeptide having the formula of cyclo (D-Trp-D-Asp-X- D-Val-Leu) , wherein X is an «-amino acid with a conformationally restricted side chain, the side chain containing 4-16 carbons, inclusive.
  • the side chain and C and if of X form 1-3, inclusive, separate or fused rings with the c and if being members of one of the rings.
  • X can be a D- or L-isomer of Tec, Tip, Oic, or Tic.
  • Tic 1,2,3,4-tetrahydro-2-carboline-3-yl-carboxylic acid
  • Step 1 Preparation of Boc-D-Trp-O-benzyl-D-Asp- Tcc-D-Val-Leu-O-Merrifield resin Tert-butyloxycarbonyl("Boc")-Leu-O-polystyrene resin (1.25 g, 0.5 mmole) was first placed in the reaction vessel of an Advanced ChemTech peptide synthesizer which was programmed to perform successively each step of the following wash-reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 min each) ; (c) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) 10% triethylamine in chloroform.
  • an Advanced ChemTech peptide synthesizer which was programmed to perform successively each step of the following wash-reaction cycle: (a) methylene chloride; (b) 33% trifluoro
  • the resulting white powder was shown to be homogeneous by both TLC and HPLC and weighed 44 mg after drying.
  • the structure of the peptide thus prepared was confirmed by amino acid analysis of acid hydrolysates and FAB-MS.
  • the structure of the peptide thus prepared was confirmed by amino acid analysis of acid hydrolysates and FAB-MS.
  • Step l Preparation of Boc-D-Trp-O-benzyl-D-Asp- Tip-Val-Leu-O-Merrifield resin Boc-Leu-O-polystyrene resin (1.25 g, 0.5 mmole) was first placed in the reaction vessel of an Advanced ChemTech peptide synthesizer which was programmed to perform successively each step of the following wash- reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 min each) ; (c) methylene chloride; (d) ethanol; (e) methylene chloride; and (f) 10% triethylamine in chloroform.
  • the resin prepared following Step 1 (1.71 g, 0.5 mmole) was mixed with anisole (5 ml) , dithiothreitol (100 mg) and anhydrous hydrogen fluoride (35 ml) at 0°C and stirred for 15 min. Excess hydrogen fluoride was evaporated rapidly under a stream of dry nitrogen and free peptide precipitated and washed with ether. The crude peptide was then dissolved in a minimum volume of 50% acetic acid and eluted on a column (2.5 x 100 cm) of Sephadex G-25 using the same solvent. Fractions containing a major component by UV absorption and Ehrlich reaction upon TLC were then pooled, evaporated to an oil.
  • cyclic pentapeptides (either with or without a carboxyl group-containing side chain in its N-terminal residue or adjacent thereto) of the invention, e.g., cyclo (D-Trp-D-Asp-Oic-D-Val-Leu)
  • cyclo D-Trp-D-Asp-Oic-D-Val-Leu
  • BIOLOGICAL ACTIVITIES To test the biological activities of the compounds of the invention, two types of assays were performed on Cyclo (D-Trp-D-Ser-Pro-D-Val-Leu) , Cyclo (D-Trp-D-Asp- Tcc-D-Val-Leu) and Cyclo (D-Trp-D-Asp-Tic-D-Val-Leu) and cyclo (D-Trp-D-Asp-Tip-D-Val-Leu) . As described below, the tested compounds were effective in abolish endothelin-induced contractions on strips- of rat uterus smooth muscle. Note that both of the assays used are well known in the art and can be used by a person of ordinary skill in the art to screen suspected compounds without undue experimentation.
  • the compounds were tested to determine their ability to displace [I 125 ] endothelin bound to the endothelin receptor. Evaluating the competitive displacement binding data, the preferred compounds are those which exhibit a high affinity (i.e., low IC 50 value) for the endothelin receptor.
  • A10 smooth muscle cells were cultured in Dulbecco's modified Eagle's medium (DMEM) without antibiotics and supplemented with 10% (vol/vol) fetal calf serum. The incubation atmosphere consisted of 10% CO 2 -90% humidified air at 37°C.
  • Male Sprague-Dawley rats 200-300 g were obtained from Taconic Farms and maintained in our animal facilities under a 12 hr light-dark cycle.
  • Crude membranes were prepared by homogenization of the AlO cells or rat cerebral cortical tissue in 20 ml of ice-cold 50 mM Tris-HCl (Buffer A) with a Brinkman Polytron (setting 6, 15 sec) . Buffer was added to obtain a final volume of 40 ml, and the homogenate was centrifuged in a Sorval SS-34 rotor at 39,000 g for 10 min at 0-4°C. The resulting supernatant was decanted and discarded. The pellet was rehomogenized in ice-cold buffer, diluted, and centrifuged as before. The final pellet was resuspended in the 50 mM Tris-HCl, containing 0.1 mg/ml bacitracin, and 0.1% BSA (Buffer B) , and held on ice for the receptor binding assay.
  • Buffer A Tris-HCl
  • Buffer B B
  • BIM-36020 was shown to be the most potent, followed by BIM-36022.
  • Cyclo D-Trp-D-Asp-Tip-D-Val-Leu
  • An endothelin agonist can be coupled to a radioactive or fluorescent label and subjected to binding to cells or tissue extracts under various conditions, thus enabling one to obtain information regarding the structure and pharmacology of the endothelin receptor.
  • Cyclic pentapeptides of the invention can be used for the treatment hypertension, nephritis, acute renal failure, cyclosporin-induced renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, asthma, atherosclerosis, cardiac
  • graft rejection •graft rejection, restenosis, endotoxin shock, endotoxin- induced multiple organ failure or disseminated intravascular coagulation in a mammalian subject.
  • a pharmaceutical composition which is suitable for parenteral administration, oral administration or external administration.
  • Such composition can be prepared by mixing the compound with solid or liquid excipient carriers known in this field.
  • Suitable pharmaceutical compositions include a liquid formulation such as an injection formulation, an inhalant formulation, a syrup formulation or an emulsion, a solid formulation such as tablets, capsules or granules, and an external drug such as an ointment or a suppository.
  • these drug formulations may contain additives which are commonly employed, such as an adjuvant, a stabilizer, a wetting agent, an emulsifier, an absorption-promoting agent or a surfactant, as the case requires.
  • distilled water for injection physiological saline, Ringer's solution, glucose, sugar syrup, gelatin, vegetable oil, cacao butter, ethylene glycol, hydroxypropyl cellulose, lactose, sucrose, corn starch, magnesium stearate and talc may be used.
  • the dose of the compound of the present invention for treating the above-mentioned diseases varies depending upon the manner of administration, the age and the body weight of the subject and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian.
  • Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount".
  • a typical administration method is oral administration or parenteral administration.
  • the daily dose in the case of oral administration is typically in the range of from 0.1 to 100 mg/kg body weight, and the daily dose in the case of parenteral administration from 0.01 to 10 mg/kg body weight.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient(s) into association with the carrier which constitutes one or more accessory ingredients.
  • the formulations for tablets or powders are prepared by uniformly and intimately blending the active ingredient with finely divided solid carriers, and then, if necessary as in the case of tablets, forming the product into the desired shape and size.
  • Formulations suitable for intravenous administration conveniently comprise sterile aqueous solutions of the active ingredient(s) .
  • the solutions are isotonic with the blood of the subject to be treated.
  • Such formulations may be conveniently prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile.
  • the formulation may be presented in unit or multi-dose containers, for example, sealed ampoules or vials.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention se rapporte à des pentapeptides cycliques de la formule: cyclo(D-Tap-D-Asp-X-D-Val-Leu) dans laquelle X représente un acide αaminé avec une chaîne latérale restreinte dans sa conformation, cette dernière contenant 4 à 16 atomes de carbone, inclusivement, ou à des sels pharmaceutiquement acceptables de ces peptides. L'invention se rapporte également à des procédés de préparation et d'utilisation de ces peptides.
PCT/US1993/002195 1992-03-12 1993-03-10 Peptides se liant au recepteur d'endotheline WO1993017701A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38021/93A AU3802193A (en) 1992-03-12 1993-03-10 Endothelin receptor-binding peptides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84987692A 1992-03-12 1992-03-12
US07/849,876 1992-03-12

Publications (1)

Publication Number Publication Date
WO1993017701A1 true WO1993017701A1 (fr) 1993-09-16

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606881A1 (fr) * 1993-01-13 1994-07-20 Takeda Chemical Industries, Ltd. Pentapeptides cycliques avec bêta-turn et gamma-turn
EP0626174A2 (fr) 1993-04-21 1994-11-30 Takeda Chemical Industries, Ltd. Procédé et composition de prophylaxie et/ou traitement de la hypofonction d'organes
WO1996008268A1 (fr) * 1994-09-14 1996-03-21 President And Fellows Of Harvard College Inhibition de l'endotheline-1 pour combattre les inflammations
EP0761682A1 (fr) * 1994-05-26 1997-03-12 Nisshin Flour Milling Co., Ltd. Cyclodepsipeptide
WO1999017756A2 (fr) * 1997-10-02 1999-04-15 Knoll Aktiengesellschaft Procede permettant d'empecher les rejets de greffes
EP0815870A3 (fr) * 1996-06-27 2000-05-03 Takeda Chemical Industries, Ltd. Composition de prophylaxie et de traitement d'infarction cérébrale
US7410951B2 (en) * 1995-04-20 2008-08-12 The University Of British Columbia Biologically active peptides and compositions, their use
WO2009046825A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide acétyl-calpastatine en tant qu'agent thérapeutique
WO2009046826A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un pentapeptide cyclique en tant qu'agent thérapeutique
WO2009046880A2 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4483850A (en) * 1982-05-10 1984-11-20 Merck & Co., Inc. N-Terminal substituted oligopeptide converting enzyme inhibitors
US4959352A (en) * 1987-09-18 1990-09-25 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
US5023233A (en) * 1989-07-28 1991-06-11 Merck & Co., Inc. Fibrinogen receptor antagonists
EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline
US5079341A (en) * 1987-07-22 1992-01-07 Galpin Ian J Cyclosporins
US5084442A (en) * 1988-09-06 1992-01-28 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
US5114918A (en) * 1989-12-28 1992-05-19 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic cyclic pentapeptides
EP0370453B1 (fr) * 1988-11-24 1994-06-15 Hoechst Aktiengesellschaft Peptides avec action inhibitrice de la bradykinine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4483850A (en) * 1982-05-10 1984-11-20 Merck & Co., Inc. N-Terminal substituted oligopeptide converting enzyme inhibitors
US5079341A (en) * 1987-07-22 1992-01-07 Galpin Ian J Cyclosporins
US4959352A (en) * 1987-09-18 1990-09-25 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
US5084442A (en) * 1988-09-06 1992-01-28 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
EP0370453B1 (fr) * 1988-11-24 1994-06-15 Hoechst Aktiengesellschaft Peptides avec action inhibitrice de la bradykinine
US5023233A (en) * 1989-07-28 1991-06-11 Merck & Co., Inc. Fibrinogen receptor antagonists
US5114918A (en) * 1989-12-28 1992-05-19 Banyu Pharmaceutical Co., Ltd. Endothelin antagonistic cyclic pentapeptides
EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965526A (en) * 1993-01-13 1999-10-12 Takeda Chemical Industries, Inc. Pentapeptide with specific conformation, its production and use
EP0953573A2 (fr) * 1993-01-13 1999-11-03 Takeda Chemical Industries, Ltd. Pentapeptide à conformation spécifique, son procédé de préparation et son utilisation
EP0606881A1 (fr) * 1993-01-13 1994-07-20 Takeda Chemical Industries, Ltd. Pentapeptides cycliques avec bêta-turn et gamma-turn
EP0626174A2 (fr) 1993-04-21 1994-11-30 Takeda Chemical Industries, Ltd. Procédé et composition de prophylaxie et/ou traitement de la hypofonction d'organes
EP0626174A3 (fr) * 1993-04-21 1996-01-03 Takeda Chemical Industries Ltd Procédé et composition de prophylaxie et/ou traitement de la hypofonction d'organes.
US6147051A (en) * 1993-04-21 2000-11-14 Takeda Chemical Industries Ltd. Methods and compositions for the prophylactic and/or therapeutic treatment of organ hypofunction
EP0761682A4 (fr) * 1994-05-26 1997-07-30 Nisshin Flour Milling Co Cyclodepsipeptide
US5801143A (en) * 1994-05-26 1998-09-01 Nisshin Flour Milling Co., Ltd. Cyclic depsipeptides useful for treatment of hyperlipemia
EP0761682A1 (fr) * 1994-05-26 1997-03-12 Nisshin Flour Milling Co., Ltd. Cyclodepsipeptide
WO1996008268A1 (fr) * 1994-09-14 1996-03-21 President And Fellows Of Harvard College Inhibition de l'endotheline-1 pour combattre les inflammations
US7772397B2 (en) 1995-04-20 2010-08-10 University Of British Columbia Biologically active peptides and compositions, their use
US7410951B2 (en) * 1995-04-20 2008-08-12 The University Of British Columbia Biologically active peptides and compositions, their use
US6251861B1 (en) 1996-06-27 2001-06-26 Takeda Chemical Industries, Ltd. Treatment of cerebral infarction using cyclic hexapeptides
EP0815870A3 (fr) * 1996-06-27 2000-05-03 Takeda Chemical Industries, Ltd. Composition de prophylaxie et de traitement d'infarction cérébrale
WO1999017756A2 (fr) * 1997-10-02 1999-04-15 Knoll Aktiengesellschaft Procede permettant d'empecher les rejets de greffes
WO1999017756A3 (fr) * 1997-10-02 1999-07-29 Knoll Ag Procede permettant d'empecher les rejets de greffes
WO2009046825A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide acétyl-calpastatine en tant qu'agent thérapeutique
WO2009046826A1 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un pentapeptide cyclique en tant qu'agent thérapeutique
WO2009046880A2 (fr) * 2007-09-11 2009-04-16 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009046880A3 (fr) * 2007-09-11 2009-05-28 Mondobiotech Lab Ag Utilisation d'un peptide en tant qu'agent thérapeutique

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