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WO1996010034A3 - Thiol-free inhibitors of farnesyl-protein transferase - Google Patents

Thiol-free inhibitors of farnesyl-protein transferase Download PDF

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Publication number
WO1996010034A3
WO1996010034A3 PCT/US1995/012224 US9512224W WO9610034A3 WO 1996010034 A3 WO1996010034 A3 WO 1996010034A3 US 9512224 W US9512224 W US 9512224W WO 9610034 A3 WO9610034 A3 WO 9610034A3
Authority
WO
WIPO (PCT)
Prior art keywords
thiol
ras
caax
inhibitors
analogs
Prior art date
Application number
PCT/US1995/012224
Other languages
French (fr)
Other versions
WO1996010034A2 (en
Inventor
Neville J Anthony
S Jane Desolms
Robert P Gomez
Samuel L Graham
John H Hutchinson
Gerald E Stokker
Original Assignee
Merck & Co Inc
Neville J Anthony
S Jane Desolms
Robert P Gomez
Samuel L Graham
John H Hutchinson
Gerald E Stokker
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
Priority claimed from US08/526,244 external-priority patent/US5652257A/en
Application filed by Merck & Co Inc, Neville J Anthony, S Jane Desolms, Robert P Gomez, Samuel L Graham, John H Hutchinson, Gerald E Stokker filed Critical Merck & Co Inc
Priority to CA 2201348 priority Critical patent/CA2201348A1/en
Priority to AU37248/95A priority patent/AU700175B2/en
Priority to JP8511933A priority patent/JPH10508005A/en
Priority to EP95935104A priority patent/EP0783517A2/en
Publication of WO1996010034A2 publication Critical patent/WO1996010034A2/en
Publication of WO1996010034A3 publication Critical patent/WO1996010034A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogs differ from those previously described as inhibitors of Ras farnesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
PCT/US1995/012224 1994-09-29 1995-09-26 Thiol-free inhibitors of farnesyl-protein transferase WO1996010034A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA 2201348 CA2201348A1 (en) 1994-09-29 1995-09-26 Thiol-free inhibitors of farnesyl-protein transferase
AU37248/95A AU700175B2 (en) 1994-09-29 1995-09-26 Thiol-free inhibitors of farnesyl-protein transferase
JP8511933A JPH10508005A (en) 1994-09-29 1995-09-26 Thiol-free farnesyl-protein transferase inhibitors
EP95935104A EP0783517A2 (en) 1994-09-29 1995-09-26 Thiol-free inhibitors of farnesyl-protein transferase

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US31497494A 1994-09-29 1994-09-29
US314,974 1994-09-29
US08/526,244 US5652257A (en) 1994-09-29 1995-09-21 Heterocycle-containing inhibitors of farnesyl-protein transferase
US526,244 1995-09-21

Publications (2)

Publication Number Publication Date
WO1996010034A2 WO1996010034A2 (en) 1996-04-04
WO1996010034A3 true WO1996010034A3 (en) 1996-05-09

Family

ID=26979651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/012224 WO1996010034A2 (en) 1994-09-29 1995-09-26 Thiol-free inhibitors of farnesyl-protein transferase

Country Status (5)

Country Link
EP (1) EP0783517A2 (en)
JP (1) JPH10508005A (en)
AU (1) AU700175B2 (en)
IL (1) IL115471A0 (en)
WO (1) WO1996010034A2 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027752A1 (en) * 1996-01-30 1997-08-07 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
JP2000507581A (en) * 1996-04-03 2000-06-20 メルク エンド カンパニー インコーポレーテッド Farnesyl-protein transferase inhibitor
CA2250460A1 (en) * 1996-04-03 1997-10-09 John H. Hutchinson Inhibitors of farnesyl-protein transferase
WO1997038665A2 (en) * 1996-04-03 1997-10-23 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
EP0891352A4 (en) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibitors of farnesyl-protein transferase
EP0904080A4 (en) * 1996-04-03 2001-08-01 Merck & Co Inc Inhibitors of farnesyl-protein transferase
US5932590A (en) * 1996-12-05 1999-08-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
DK1572127T4 (en) 2002-02-14 2014-11-24 Univ Leland Stanford Junior Enzyme processing of foods for celiac disease
US8143210B2 (en) 2002-02-14 2012-03-27 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
AU2003234597A1 (en) * 2002-05-14 2003-12-02 The Board Of Trustees Of The Leland Stanford Junior University Drug therapy for celiac sprue
AU2003294473A1 (en) 2002-11-20 2004-06-15 The Board Of Trustees Of The Leland Stanford Junior University Diagnostic method for celiac sprue
US7579313B2 (en) 2003-11-18 2009-08-25 The Board Of Trustees Of The Leland Stanford Junior University Transglutaminase inhibitors and methods of use thereof
CA2680590C (en) 2007-03-16 2017-10-17 Jonathan David Gass Combination enzyme therapy for digestion of dietary gluten

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016340A1 (en) * 1990-04-18 1991-10-31 Board Of Regents, The University Of Texas System Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase
WO1995009000A1 (en) * 1993-09-30 1995-04-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1995012612A1 (en) * 1993-11-05 1995-05-11 Warner-Lambert Company Substituted di- and tripeptide inhibitors of protein:farnesyl transferase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991016340A1 (en) * 1990-04-18 1991-10-31 Board Of Regents, The University Of Texas System Methods and compositions for the identification, characterization and inhibition of farnesyl protein transferase
WO1995009000A1 (en) * 1993-09-30 1995-04-06 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1995012612A1 (en) * 1993-11-05 1995-05-11 Warner-Lambert Company Substituted di- and tripeptide inhibitors of protein:farnesyl transferase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JAMES, G.L.ET AL.: "Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells", SCIENCE, vol. 260, 25 June 1993 (1993-06-25), pages 1937 - 1942 *

Also Published As

Publication number Publication date
EP0783517A2 (en) 1997-07-16
AU3724895A (en) 1996-04-19
JPH10508005A (en) 1998-08-04
IL115471A0 (en) 1995-12-31
AU700175B2 (en) 1998-12-24
WO1996010034A2 (en) 1996-04-04

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