WO2000020440A1 - Caspases et apoptose - Google Patents

Caspases et apoptose Download PDF

Info

Publication number
WO2000020440A1
WO2000020440A1 PCT/US1999/023271 US9923271W WO0020440A1 WO 2000020440 A1 WO2000020440 A1 WO 2000020440A1 US 9923271 W US9923271 W US 9923271W WO 0020440 A1 WO0020440 A1 WO 0020440A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
acetyl
apoptosis
aspartylglutamylvalylaspartic
excessive
Prior art date
Application number
PCT/US1999/023271
Other languages
English (en)
Inventor
Dennis Lee
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP99953073A priority Critical patent/EP1129108A4/fr
Priority to JP2000574551A priority patent/JP2003524603A/ja
Publication of WO2000020440A1 publication Critical patent/WO2000020440A1/fr

Links

Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is to the discovery of a new method to block excessive or inappropriate apoptosis in a mammal.
  • necrosis is usually the result of severe trauma and is a process that involves loss of membrane integrity and uncontrolled release of cellular contents, often giving rise to inflammatory responses.
  • apoptosis is a more physiological process that occurs in a controlled manner and is generally noninflammatory in nature. For this reason apoptosis is often referred to as programmed cell death.
  • the name itself (apoptosis: Greek for "dropping off", for example leaves from trees) implies a cell death that is part of a normal physiological process (Kerr et al., Br. J. Cancer, 26: 239-257 (1972)).
  • Apoptosis appears to be a carefully controlled series of cellular events which ultimately leads to death of the cell. This process for elimination of unwanted cells is active and requires expenditure of cellular energy.
  • the morphological characteristics of apoptosis include cell shrinkage and loss of cell-cell contact, condensation of nuclear chromatin followed by fragmentation, the appearance of membrane ruffling, membrane blebbing and apoptotic bodies. At the end of the process, neighboring cells and macrophages phagocytose the fragments from the apoptotic cell. The process can be very fast, occurring in as little as a few hours (Bright et al., Biosci. Rep., 14: 67-82 (1994)).
  • the best defined biochemical event of apoptosis involves the orderly destruction of nuclear DNA.
  • Signals for apoptosis promote the activation of specific calcium- and magnesium-dependent endonucleoases that cleave the double stranded DNA at linker regions between nucleosomes. This results in production of DNA fragments that are multiples of 180-200 base pair fragments (Bergamaschi et al., Haematologica, 79: 86-93 (1994): Stewart, JNCI, 86: 1286-1296 (1994)). When examined by agarose gel electrophoresis, these multiple fragments form a ladder pattern that is characteristic for most cells undergoing apoptosis.
  • TNFa tumor necrosis factor
  • growth factor deprivation some viral proteins
  • radiation and anticancer drugs Some of these stimuli can induce their signals through a variety of cell surface receptors, such as the TNF / nerve growth factor family of receptors, which include CD40 and Fas/Apo-1 (Bright et al., supra).
  • TNF / nerve growth factor family of receptors which include CD40 and Fas/Apo-1 (Bright et al., supra).
  • genes that appear to be required for induction of apoptosis are Ced-3 and Ced-4. These genes must function in the dying cells and, if either gene is inactivated by mutation, cell death fails to occur (Yuan et al., Devel. Biol., 138: 33-41 (1990)).
  • genes that have been linked with induction of apoptosis include the proto-oncogene c-myc and the tumor suppresser gene p53 (Bright et al., supra; Symonds et al., Cell, 78: 703-71 1 (1994)).
  • Ced-9 An example in C. elegans is Ced-9. When it is abnormally activated, cells survive that would normally die and, conversely, when Ced-9 is inactivated cells die that would normally live (Stewart, B.W., supra).
  • bcl-2 A mammalian counterpart is bcl-2, which had been identified as a cancer-causing oncogene. This gene inhibits apoptosis when its product is overexpressed in a variety of mammalian cells, rendering them less sensitive to radiation, cytotoxic drugs and apoptotic signals such as c-myc (Bright et al., supra).
  • Apoptosis is an important part of normal physiology. The two most often sited examples of this are fetal development and immune cell development. In development of the fetal nervous system, over half of the neurons that exist in the early fetus are lost by apoptosis during development to form the mature brain (Bergamaschi et al., Haematologica, 79: 86-93 (1994)). In the production of immune competent T cells (and to a lesser extent evidence exists for B cells), a selection process occurs that eliminates cells that recognize and react against self This selection process is thought to occur in an apoptotic manner within areas of immune cell maturation (Williams, G T., J. Pathol., 173 1-4 (1994): Krammer et al.. Curr. Opin. Immunol . 6 279-289 (1994)).
  • Dysregulation of apoptosis can play an important role in disease states, and diseases can be caused by both excessive or too little apoptosis occurring
  • diseases associated with too little apoptosis would be certain cancers
  • There is a follicular B-cell lymphoma associated with an aberrant expression of functional bcl-2 and an inhibition of apoptosis in that cell (Bergamaschi et al , supra)
  • p53 associated with the inhibition of apoptosis and the production of cancerous cells
  • one example of excessive or inappropriate apoptosis is the loss of neuronal cells that occurs in Alzheimer disease, possible induced by b-amyloid peptides (Barr et al., BioTechnology, 12' 487-493 (1994)).
  • apoptosis is the loss of neurons and ohgondendrogha that occur in traumatic spinal cord injury ((Springer er al) Nature Medicine 5 943-946 1999)).
  • Other examples include excessive apoptosis of CD4 + T cells that occurs in HIV infection, of cardiac myocytes during infarction / reperfusion and of neuronal cells during ischemia (Bergamaschi et al , supra); Barr et al , supra).
  • Some pharmacological agents attempt to counteract the lack of apoptosis that is observed in cancers.
  • examples include topoisomerase II inhibitors, such as the epipodophyllotoxins, and antimetabohtes, such as ara-c, which have been reported to enhance apoptosis in cancer cells (Ashwell et al , supra) In many cases with these anti- cancer drugs, the exact mechanism for the induction of apoptosis remains to be elucidated.
  • halo or halogens, is used herein to include, unless otherwise specified, chloro, fluoro, bromo and iodo.
  • Acetyl-aspartylglutamylvalylaspaitic acid (5-benzoylaminomethylthiophene)-2- sulfonamidomethylketone
  • E.coli cells were lysed in 10 ml/g of cells of lysis buffer (50 mM Na phosphate pH 7.2, 0.1 M NaCl, 0.1 % Tween 20, and 10 mM b-mercaptoethanol) using Microfluidics Ml 10Y homogenizer at 10,000 psi. After centrifugation, Caspase 3 activity was detected in lysate supernatant.
  • lysis buffer 50 mM Na phosphate pH 7.2, 0.1 M NaCl, 0.1 % Tween 20, and 10 mM b-mercaptoethanol
  • Caspase 3 was assayed at 30 degrees C in 96-well plates using the fluorogenic tetrapeptide substrate N-acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartyl-7-amido-4- methylcoumarin (Ac-DEVD-AMC).
  • the assays were conducted at pH 7.5 in a buffered system containing 25 mM Hepes, 10% sucrose, 0.1 % CHAPS, and 1-50 uM DTT. The concentration of substrate was fixed at 10 uM. Fluorescence of the liberated 7-amino-4- methylcoumarin was continuously monitored at 460 nm following excitation at 360 nm.
  • DMSO dimethylsulf oxide
  • Jurkat cells were obtained from American Type Culture Collection and grown in RPMI-1640 media supplemented with 10% fetal bovine serum at 37°, 5% C0 2 . Cells were seeded in T-flasks at 0.03 to 0.08 x 10" cells / ml and used for experiments at 0.5 to 1.0 x 10" cells / ml. Other proliferative cells can be used with apoptosis induced by anti-fas, campto hecine, cerimide or TNF.
  • a method for measuring apoptosis is to quantitate the amount of broken DNA fragments using a fluorescent end-labeling method, a system used in the ApopTag kit from Oncor (Gaithersburg, MD).
  • the enzyme terminal deoxynucleotidyl transferase extends the DNA fragments with digoxigenin-containing nucleotides, which are then dected with an antidigoxigenin antibody earring fluorescein to allow dection by fluorescence (494 nm excitation and 523 nm emission).
  • Propidium iodide is used as counter stain to measure total DNA content.
  • Flow cytometric analysis was done on Becton-Dickinson (Rutherfor, NJ) FACScan instrument using CellQuest software.
  • the compounds of the present invention will generally be administered in a standard pharmaceutical composition obtained by admixture with a pharmaceutical carrier or diluent selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier or diluent selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsule, ovules or lozenges either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents.
  • They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the choice of form for administration as well as effective dosages will vary depending, inter alia, on the condition being treated. The choice of mode of administration and dosage is within the skill of the art.
  • the compounds of the present invention can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerin, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • the composition is in unit dose form such as a tablet or capsule.
  • Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.
  • Another aspect of the present invention is the inhibition of apoptosis as a novel therapy to treat osteoarthritis, using compounds of Formula (I) as defined herein.
  • apoptosis as a novel therapy to treat osteoarthritis, using compounds of Formula (I) as defined herein.
  • Recent evidence shows that chronic, degenerative conditions of the liver are linked to hepatocellular apoptosis. These conditions include chemical-, infectious- and immune/inflammatory-induced hepatocellular degeneration.
  • Apoptosis of liver cells has been observed in liver degenerative states induced by a variety of chemical agents, including acetaminophen (Ray, et a l.,(1993) FASEB. J.
  • Human peripheral blood monocytes are isolated and purified from either blood bank buffy coats or platelet pheresis residues, according to the procedure of Colotta, R. et al., J Immunol, 132(2), 936 (1984).
  • the monocytes are plated at a density of 1x10 ⁇ cells/ml medium/well in 24-well multi-dishes. The cells are allowed to adhere for 1 hour after which time the supernatant is aspirated and fresh medium (1ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA) containing 1% fetal calf serum plus penicillin and streptomycin (10 units/ml) added.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne de nouveaux composés représentés par la formule (I), leurs compositions pharmaceutiques, ainsi qu'une nouvelle forme d'inhibition des caspases utile dans le traitement de l'apoptose et des états pathologiques provoqués par une mort cellulaire excessive ou inappropriée.
PCT/US1999/023271 1998-10-06 1999-10-06 Caspases et apoptose WO2000020440A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99953073A EP1129108A4 (fr) 1998-10-06 1999-10-06 Caspases et apoptose
JP2000574551A JP2003524603A (ja) 1998-10-06 1999-10-06 カスパーゼおよびアポトーシス

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10342898P 1998-10-06 1998-10-06
US60/103,428 1998-10-06

Publications (1)

Publication Number Publication Date
WO2000020440A1 true WO2000020440A1 (fr) 2000-04-13

Family

ID=22295125

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/023271 WO2000020440A1 (fr) 1998-10-06 1999-10-06 Caspases et apoptose

Country Status (3)

Country Link
EP (1) EP1129108A4 (fr)
JP (1) JP2003524603A (fr)
WO (1) WO2000020440A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1773348A2 (fr) * 2004-07-12 2007-04-18 Idun Pharmaceuticals, Inc. Analogues de tetrapeptide
US7709370B2 (en) 2007-09-20 2010-05-04 International Business Machines Corporation Spin-on antireflective coating for integration of patternable dielectric materials and interconnect structures
US8084862B2 (en) 2007-09-20 2011-12-27 International Business Machines Corporation Interconnect structures with patternable low-k dielectrics and method of fabricating same
WO2012019003A1 (fr) 2010-08-06 2012-02-09 Bristol-Myers Squibb Company Dérivés d'oxoacétyl pipérazinamide à substitution indole et azaindole
US8618663B2 (en) 2007-09-20 2013-12-31 International Business Machines Corporation Patternable dielectric film structure with improved lithography and method of fabricating same
WO2021097980A1 (fr) * 2019-11-22 2021-05-27 中国药科大学 Inhibiteur de caspase-3 et son utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055451A (en) * 1986-12-22 1991-10-08 Syntex Inc. Aryloxy and arylacyloxy methyl ketones as thiol protease inhibitors

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995005192A1 (fr) * 1993-08-13 1995-02-23 Merck & Co., Inc. DERIVES SUBSTITUES DE CETONE 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
GB2292149A (en) * 1994-08-09 1996-02-14 Ferring Res Ltd Peptide inhibitors of pro-interleukin-1beta converting enzyme
JP2001508404A (ja) * 1996-10-11 2001-06-26 ワーナー―ランバート・コンパニー スルホンアミドインターロイキン―１β変換酵素阻害剤
US7247438B1 (en) * 1997-02-18 2007-07-24 Dana-Farber Cancer Institute Methods of identifying agents which enhance caspase activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5055451A (en) * 1986-12-22 1991-10-08 Syntex Inc. Aryloxy and arylacyloxy methyl ketones as thiol protease inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1129108A4 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1773348A2 (fr) * 2004-07-12 2007-04-18 Idun Pharmaceuticals, Inc. Analogues de tetrapeptide
EP1773348A4 (fr) * 2004-07-12 2009-05-20 Idun Pharmaceuticals Inc Analogues de tetrapeptide
EP2457896A1 (fr) * 2004-07-12 2012-05-30 Idun Pharmaceuticals, Inc. Tripeptides en tant que modulateurs de la caspase
US7709370B2 (en) 2007-09-20 2010-05-04 International Business Machines Corporation Spin-on antireflective coating for integration of patternable dielectric materials and interconnect structures
US7944055B2 (en) 2007-09-20 2011-05-17 International Business Machines Corporation Spin-on antireflective coating for integration of patternable dielectric materials and interconnect structures
US8084862B2 (en) 2007-09-20 2011-12-27 International Business Machines Corporation Interconnect structures with patternable low-k dielectrics and method of fabricating same
US8450854B2 (en) 2007-09-20 2013-05-28 International Business Machines Corporation Interconnect structures with patternable low-k dielectrics and method of fabricating same
US8618663B2 (en) 2007-09-20 2013-12-31 International Business Machines Corporation Patternable dielectric film structure with improved lithography and method of fabricating same
US9484248B2 (en) 2007-09-20 2016-11-01 Globalfoundries Inc. Patternable dielectric film structure with improved lithography and method of fabricating same
WO2012019003A1 (fr) 2010-08-06 2012-02-09 Bristol-Myers Squibb Company Dérivés d'oxoacétyl pipérazinamide à substitution indole et azaindole
WO2021097980A1 (fr) * 2019-11-22 2021-05-27 中国药科大学 Inhibiteur de caspase-3 et son utilisation

Also Published As

Publication number Publication date
EP1129108A1 (fr) 2001-09-05
JP2003524603A (ja) 2003-08-19
EP1129108A4 (fr) 2002-01-09

Similar Documents

Publication Publication Date Title
EP0276436B1 (fr) Dérivés de l'acide phosphénique
CA2306692C (fr) Dipeptides inhibiteurs de l'apoptose et utilisation de ces derniers
US6403792B1 (en) Sulfonyl isatin compounds and methods of blocking apoptosis therewith
EP0988035B1 (fr) Caspases et apoptose
US5919790A (en) Hydroxamate inhibitors of interleukin-1β converting enzyme
EP1054667A1 (fr) Composes chimiques
EP0859779A1 (fr) Enzyme de conversion d'interleukine et apoptose
US7465721B2 (en) 2-hydroxytetrahydrofuran derivatives and use thereof as medicaments
US6514992B1 (en) Caspases and apoptosis
CA2126687A1 (fr) Derives de substitution peptidyliques renfermant de l'acide phosphonique, agents antidegeneratifs
EP1129108A1 (fr) Caspases et apoptose
WO2001022966A1 (fr) Caspases et apoptose
EP0851760A1 (fr) Enzyme de conversion d'interleukines et apoptose
US6649593B1 (en) Modulators of SREBP processing
MXPA00004970A (en) N-[2-(5-benzyloxycarbonyl-amino-6-oxo-2-(4- fluorophenyl)-1,6-dihydro -1-pyrimidinyl)aceto- xyl]-l-aspartic acid aldehyde as an i(in vivo) inhibitor of interleukin-1b converting enzyme (ice)
MXPA00003260A (en) Dipeptide apoptosis inhibitors and the use thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 09806121

Country of ref document: US

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 574551

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999953073

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999953073

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1999953073

Country of ref document: EP