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WO1993014777A1 - DERIVES DE PEPTIDYLE UTILES COMME INHIBITEURS DE L'ENZYME TRANSFORMANT L'INTERLEUKINE-1$g(b) - Google Patents

DERIVES DE PEPTIDYLE UTILES COMME INHIBITEURS DE L'ENZYME TRANSFORMANT L'INTERLEUKINE-1$g(b) Download PDF

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Publication number
WO1993014777A1
WO1993014777A1 PCT/US1993/000481 US9300481W WO9314777A1 WO 1993014777 A1 WO1993014777 A1 WO 1993014777A1 US 9300481 W US9300481 W US 9300481W WO 9314777 A1 WO9314777 A1 WO 9314777A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
amino
hydroxy
substituted
aryl
Prior art date
Application number
PCT/US1993/000481
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English (en)
Inventor
Kevin T. Chapman
Malcolm Maccoss
William H. Parsons
Original Assignee
Merck & Co., Inc.
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 Merck & Co., Inc. filed Critical Merck & Co., Inc.
Publication of WO1993014777A1 publication Critical patent/WO1993014777A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/12—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom
    • C07C245/14—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C245/18—Diazo compounds, i.e. compounds having the free valencies of >N2 groups attached to the same carbon atom having diazo groups bound to acyclic carbon atoms of a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to substituted peptidyl derivatives useful in the treatment of inflammation in lung, central nervous system, kidney, joints, endocardium, pericardium, eyes, ears, skin, gastrointestinal tract and urogenital system. More particularly, this invention relates substituted peptidyl lactones and open forms thereof that are useful inhibitors of interleukin-1 ⁇ converting enzyme (ICE). Interleukin-1 ⁇ converting enzyme (ICE) has been identified as the enzyme responsible for ICE.
  • ICE Interleukin-1 ⁇ converting enzyme
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-1 Mammalian interleukin-1 (IL-1) is an
  • the primary cell type responsible for IL-1 production is the
  • peripheral blood monocyte Other cell types have also been described as releasing or containing IL-1 or IL-1 like molecules. These include epithelial cells (Luger, et al., J. Immunol. 127: 1493-1498 (1981), Le et al., J. Immunol. 138: 2520-2526 (1987) and Lovett and Larsen, J. Clin. Invest. 82: 115-122 (1988), connective tissue cells (Ollivierre et al., Biochem. Biophys. Res. Comm. 141: 904-911 (1986), Le et al, J. Immunol. 138: 2520-2526 (1987), cells of neuronal origin (Giulian et al., J. Esp. Med. 164:594-604 (1986) and leukocytes (Pistoia et al., J.
  • Biologically active IL-1 exists in two distinct forms, IL-l ⁇ with an isoelectric point of about pI 5.2 and IL-1 ⁇ with an isoelectric point of about 7.0 with both forms having a molecular mass of about 17,500 (Bayne et al., J. Esp. Med. 163:
  • Mammalian IL-1 ⁇ is synthesized as a cell associated precursor polypeptide with a molecular mass of about 31.4 kDa (Limjuco et al., Proc. Natl. Acad. Sci USA 83: 3972-3976 (1986).
  • Precursor IL-1 ⁇ is unable to bind to IL-1 receptors and is
  • Mammalian cells capable of producing IL-1 ⁇ include, but are not limited to, karatinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes, astrocytes, glioma cells, mononuclear phagocytes, granulocytes, T and B lymphocytes and NK cells.
  • interleukin-1 interleukin-1
  • proteolysis inducing factor stimulates muscle cells to. produce
  • IL-1 has multiple effects on cells involved in inflammation and wound healing. Subcutaneous injection of IL-1 leads to margination of neutrophils and maximal extravascular infiltration of the
  • PMN polymorphonuclear leukocytes
  • macrophages have been reported to be chemotactically attracted to IL-1 to produce prostaglandins in response to IL-1 and to exhibit a more prolonged and active tumoricidal state.
  • IL-1 is also a potent bone resorptive agent capable upon infusion into mice of causing
  • disease states in which the ICE inhibitors of Formula I may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis;
  • infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or
  • Immune-based diseases which may be responsive to ICE inhibitors of Formula I include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host-disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis.
  • ICE inhibitors of Formula I may also be useful in the treatment of bone and cartilage
  • ICE inhibitors of Formula I may also be useful in treatment of certain tumors which produce IL 1 as an autocrine growth factor and in preventing the cachexia associated with certain tumors.
  • Novel peptidyl derivatives formula I are found to be potent inhibitors of interleukin-1 ⁇ converting enzyme (ICE).
  • Compounds of formula I are useful in the treatment of deseases including
  • the invention encompasses compounds of formula I..
  • aryl C 1-6 alkyl wherein the aryl group is selected from the group consisting of: (1) phenyl,
  • substitutents are independently C 1-6 alkyl, halo, hydroxy, C 1-6 alkyl amino, C 1-6 alkoxy, C 1-6 alkylthio, and
  • AA 1 is independently selected from the group
  • R 7 is selected from the group
  • aryl is defined as immediately, above, and wherein the aryl may be mono and di-substituted, the substituents being each independently C 1-6 alkyl, halo, hydroxy, C 1-6 alkyl amino, C 1-6 alkoxy,
  • AA 2 is independently selected from the group
  • R 8 and R 9 are each independently selected from the group consisting of
  • aryl is defined as immediately above, and wherein the aryl may be mono and di-substituted, the substituents being each independently C 1-6 alkyl, halo, hydroxy, C 1-6 alkyl amino, C 1-6 alkoxy,
  • AA 1 is independently selected from the group
  • R 7 is aryl C 1-6 alkyl
  • aryl is defined as immediately above, and wherein the aryl may be mono and di-substituted , the substituents being each independently C 1-6 alkyl, halo, hydroxy, C 1-6 alkyl amino, C 1-6 alkoxy,
  • AA 2 is independently selected from the group
  • R 3 and R 9 are each independently selected from the group consisting of
  • aryl is defined as immediately above, and wherein the aryl may be mono and di-substituted, the substituents being each independently C 1-6 alkyl, halo, hydroxy, C 1-6 alkyl amino, C 1-6 alkoxy,
  • AA1, AA2 and AA3 are each independently selected from the group consisting of the L- and D- forms of the amino acids including glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, asparagine, glutamic acid, glutamine, lysine, hydroxy-lysine, histidine, arginine, phenylala ⁇ ine, tyrosine, tryptophan, cysteine, methionine,
  • ornithine ß-alanine, homoserine, homotyrosine, homophenylalanine and citrulline.
  • R 1 is C 1-3 alkyl
  • R 8 and R 9 are each individually
  • aryl C 1-6 alkyl wherein the aryl group is selected from phenyl and indolyl, and the aryl group may be substituted with hydroxy, C 1-3 alkyl.
  • R 1 is methyl
  • R 8 is C 1-6 alkyl
  • This invention also concerns to
  • compositions and methods of treatment of interleukin-1 and interleukin-1 ⁇ mediated or implicated disorders or diseases comprising
  • interleukin-1 ⁇ inhibitors of formula (I) as the active constituents.
  • this invention concerns pharmaceutical compositions and methods of treatment of diseases selected from septic shock, allograft rejection, inflammatory bowel disease and rheumatoid arthritis in a patient in need of such treatment comprising:
  • the tetrapeptide diazomethylketone can be prepared as follows. FMOC-aspartic acid ⁇ -methyl ester is converted to its diazomethylketone as before. The FMOC group is then removed with
  • This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat, or fur industries or as pets) suffering from disorders or diseases which can be attributed to IL-1/ICE as previously described, and more specifically, a method of
  • IL-1/ICE inhibitors of formula (I) as the active constituents.
  • disease states in which the ICE inhibitors of Formula I may be useful as therapeutic agents include, but are not limited to, infectious diseases where active infection exists at any body site, such as meningitis and salpingitis;
  • infections including septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody, and/or
  • Immune-based diseases which may be responsive to ICE inhibitors of Formula I include but are not limited to conditions involving T-cells and/or macrophages such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host-disease; auto-immune diseases including Type I diabetes mellitus and multiple sclerosis.
  • ICE inhibitors of Formula I may also be useful in the treatment of bone and cartilage
  • ICE inhibitors of Formula I may also be useful in treatment of certain tumors which produce IL 1 as an autocrine growth factor and in preventing the cachexia associated with certain tumors.
  • parenteral as used herein
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and
  • Formulations for oral use may also be
  • the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring .
  • phosphatide for example lecithin
  • condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol
  • anhydrides for example polyethylene sorbitan
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a
  • thickening agent for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example
  • sweetening, flavoring and coloring agents may also be present.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, .or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum
  • tragacanth naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol
  • anhydrides for example sorbitan monooleate
  • condensation products of the said partial esters with ethylene oxide for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain
  • sweetening and flavoring agents are sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be
  • the sterile injectable preparation may also be a sterile
  • injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find usein the preparation of injectables.
  • the compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (I) are employed.
  • topical application shall include mouth washes and gargles.
  • Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 2.5 mg to about 7 gms. per patient per day).
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 gms per patient per day).
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 gm of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux dérivés de peptidyle de la formule (I) qui se révèlent être de puissants inhibiteurs de l'enzyme transformant l'interleukine-1β (ETI). Des composés de la formule (I) peuvent être utiles dans le traitement d'affections inflammatoires ou déficits immunitaires des poumons et des voies respiratoires; du système nerveux central et de ses membranes environnantes; des yeux et des oreilles; des articulations, des os et des tissus conjonctifs; du système cardiovasculaire et du péricarde; des systèmes gastrointestinaux et urogénitaux; de la peau et des muqueuses. Des composés de la formule (I) sont également utiles dans le traitement des complications d'infections (par ex., le choc toxi-infectieux à germes Gram négatif) et de tumeurs dans lesquelles l'IL 1 agit comme un facteur de croissance autocrine ou comme un médiateur de cachexie.
PCT/US1993/000481 1992-01-31 1993-01-21 DERIVES DE PEPTIDYLE UTILES COMME INHIBITEURS DE L'ENZYME TRANSFORMANT L'INTERLEUKINE-1$g(b) WO1993014777A1 (fr)

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US83016292A 1992-01-31 1992-01-31
US830,162 1992-01-31

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995035308A1 (fr) * 1994-06-17 1995-12-28 Vertex Pharmaceuticals Incorporated INHIBITEURS DE L'ENZYME DE CONVERSION D'INTERLEUKINE-1$g(b)
US5656627A (en) * 1994-06-17 1997-08-12 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US5776718A (en) * 1995-03-24 1998-07-07 Arris Pharmaceutical Corporation Reversible protease inhibitors
US5843904A (en) * 1995-12-20 1998-12-01 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1βconverting enzyme
US5847135A (en) * 1994-06-17 1998-12-08 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US5968927A (en) * 1996-09-20 1999-10-19 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US5976858A (en) * 1994-02-25 1999-11-02 Arris Pharmaceuticals Irreversible cysteine protease inhibitors containing vinyl groups conjugated to electron withdrawing groups
US6008217A (en) * 1995-12-20 1999-12-28 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US6184244B1 (en) 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6204261B1 (en) 1995-12-20 2001-03-20 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β Converting enzyme inhibitors
US6288037B1 (en) 1996-01-29 2001-09-11 Basf Aktiengesellschaft Substrates and inhibitors for cysteine protease ICH-1
US6372885B1 (en) 1996-10-22 2002-04-16 Peptide Therapeutics Limited Solid-phase technology for the preparation of amides
US6426413B1 (en) 1998-03-09 2002-07-30 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US7288624B2 (en) 1994-06-17 2007-10-30 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US7417029B2 (en) 2000-05-19 2008-08-26 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US7531570B2 (en) 2004-05-27 2009-05-12 Vertex Pharmaceuticals Incorporated Treatment of diseases using ICE inhibitors
EP2241328A1 (fr) 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies
US9116157B2 (en) 2010-11-05 2015-08-25 Brandeis University Ice-cleaved alpha-synuclein as a biomarker
US9352010B2 (en) 2011-07-22 2016-05-31 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
EP3603634A1 (fr) 2004-05-18 2020-02-05 Novartis AG Composition pharmaceutique comprenant du glycopyrrolate et un agoniste du récepteur beta2 adrénergique
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015577A1 (fr) * 1990-04-04 1991-10-17 Black, Roy, A. INTERLEUKIN 1'beta' PROTEASE

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015577A1 (fr) * 1990-04-04 1991-10-17 Black, Roy, A. INTERLEUKIN 1'beta' PROTEASE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF BIOLOGICAL CHEMISTRY, Volume 265, No. 24, issued 25 August 1990, SLEATH et al., "Substrate Specificity of the Protease that Processes Human Interleukin-1B", pages 14526-14528. *

Cited By (59)

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Publication number Priority date Publication date Assignee Title
US5976858A (en) * 1994-02-25 1999-11-02 Arris Pharmaceuticals Irreversible cysteine protease inhibitors containing vinyl groups conjugated to electron withdrawing groups
US6287840B1 (en) 1994-02-25 2001-09-11 Axys Pharmaceuticals, Inc. Irreversible cysteine protease inhibitors containing vinyl groups conjugated to electron withdrawing groups
WO1995035308A1 (fr) * 1994-06-17 1995-12-28 Vertex Pharmaceuticals Incorporated INHIBITEURS DE L'ENZYME DE CONVERSION D'INTERLEUKINE-1$g(b)
US5716929A (en) * 1994-06-17 1998-02-10 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US6025147A (en) * 1994-06-17 2000-02-15 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1 β converting enzyme
EP2123665A2 (fr) 1994-06-17 2009-11-25 Vertex Pharmaceuticals Incorporated Inhibiteurs de l'enzyme de conversion d'interleukine-1Beta
US5847135A (en) * 1994-06-17 1998-12-08 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
US7772366B2 (en) 1994-06-17 2010-08-10 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
CZ298625B6 (cs) * 1994-06-17 2007-11-28 Vertex Pharmaceuticals Incorporated Inhibitory enzymu konvertujícího interleukin-1beta, zpusob jejich selekce a farmaceutické prostredky, které je obsahují
US5756466A (en) * 1994-06-17 1998-05-26 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
US7288624B2 (en) 1994-06-17 2007-10-30 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
AP797A (en) * 1994-06-17 2000-01-07 Vertex Pharma Inhibitors of interleukin-1B converting enzyme.
US5656627A (en) * 1994-06-17 1997-08-12 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1β converting enzyme
EP1394175A1 (fr) * 1994-06-17 2004-03-03 Vertex Pharmaceuticals Incorporated inhibiteur de l'enzyme de conversion de l'interleukine 1 beta
US6103711A (en) * 1994-06-17 2000-08-15 Vertex Pharmaceuticals, Incorporated Inhibitors of interleukin-1β converting enzyme
US5776718A (en) * 1995-03-24 1998-07-07 Arris Pharmaceutical Corporation Reversible protease inhibitors
US6258948B1 (en) 1995-12-20 2001-07-10 Vertex Pharmaceuticals, Incorporated Inhibitors of Interleukin-1β converting enzyme
EP2083014A2 (fr) 1995-12-20 2009-07-29 Vertex Pharmceuticals Incorporated Inhibiteurs d'enzyme à conversion d'interleukine-1ß
US5843904A (en) * 1995-12-20 1998-12-01 Vertex Pharmaceuticals, Inc. Inhibitors of interleukin-1βconverting enzyme
US6204261B1 (en) 1995-12-20 2001-03-20 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β Converting enzyme inhibitors
US6162790A (en) * 1995-12-20 2000-12-19 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US5874424A (en) * 1995-12-20 1999-02-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US7790713B2 (en) 1995-12-20 2010-09-07 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6423840B1 (en) 1995-12-20 2002-07-23 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
EP2295442A2 (fr) 1995-12-20 2011-03-16 Vertex Pharmaceuticals Incorporated Inhibiteurs d'enzyme à conversion d'interleukine-1ß
US6008217A (en) * 1995-12-20 1999-12-28 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US8119631B2 (en) 1995-12-20 2012-02-21 Vertex Pharmaceuticals Incorporated Inhibitors of interleukin-1β converting enzyme
US6288037B1 (en) 1996-01-29 2001-09-11 Basf Aktiengesellschaft Substrates and inhibitors for cysteine protease ICH-1
US6444663B2 (en) 1996-09-20 2002-09-03 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US5968927A (en) * 1996-09-20 1999-10-19 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US6187771B1 (en) 1996-09-20 2001-02-13 Idun Pharmaceuticals, Inc. Tricyclic compounds for the inhibition of the ICE/ced-3 protease family of enzymes
US6372885B1 (en) 1996-10-22 2002-04-16 Peptide Therapeutics Limited Solid-phase technology for the preparation of amides
US6489353B2 (en) 1996-12-16 2002-12-03 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6184244B1 (en) 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
US6054487A (en) * 1997-03-18 2000-04-25 Basf Aktiengesellschaft Methods and compositions for modulating responsiveness to corticosteroids
US6426413B1 (en) 1998-03-09 2002-07-30 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US7358273B2 (en) 1998-03-19 2008-04-15 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
EP2011800A2 (fr) 1998-03-19 2009-01-07 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
US8691848B2 (en) 1998-03-19 2014-04-08 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
EP2261233A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
EP2261232A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
EP2261235A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
EP2261234A2 (fr) 1998-03-19 2010-12-15 Vertex Pharmaceuticals Incorporated Inhibiteurs de caspase
EP2241328A1 (fr) 2000-05-12 2010-10-20 Immunex Corporation Inhibiteurs d'interleukine 1 dans le traitement de maladies
US8022041B2 (en) 2000-05-19 2011-09-20 Vertex Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US9156880B2 (en) 2000-05-19 2015-10-13 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US9994613B2 (en) 2000-05-19 2018-06-12 Vertex Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US9487555B2 (en) 2000-05-19 2016-11-08 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
US8329662B2 (en) 2000-05-19 2012-12-11 Vertexd Pharmaceuticals Incorporated Prodrug of an ICE inhibitor
US7417029B2 (en) 2000-05-19 2008-08-26 Vertex Pharmaceuticals Incorporated Prodrug of an ice inhibitor
EP2270005A1 (fr) 2000-05-19 2011-01-05 Vertex Pharmceuticals Incorporated Promédicament inhibiteur d'ECI
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
EP3603634A1 (fr) 2004-05-18 2020-02-05 Novartis AG Composition pharmaceutique comprenant du glycopyrrolate et un agoniste du récepteur beta2 adrénergique
US7531570B2 (en) 2004-05-27 2009-05-12 Vertex Pharmaceuticals Incorporated Treatment of diseases using ICE inhibitors
US9116157B2 (en) 2010-11-05 2015-08-25 Brandeis University Ice-cleaved alpha-synuclein as a biomarker
US9352010B2 (en) 2011-07-22 2016-05-31 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
US9956260B1 (en) 2011-07-22 2018-05-01 The J. David Gladstone Institutes Treatment of HIV-1 infection and AIDS
US11021514B2 (en) 2016-06-01 2021-06-01 Athira Pharma, Inc. Compounds

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