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WO1994007507A1 - Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate - Google Patents

Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate Download PDF

Info

Publication number
WO1994007507A1
WO1994007507A1 PCT/US1993/008168 US9308168W WO9407507A1 WO 1994007507 A1 WO1994007507 A1 WO 1994007507A1 US 9308168 W US9308168 W US 9308168W WO 9407507 A1 WO9407507 A1 WO 9407507A1
Authority
WO
WIPO (PCT)
Prior art keywords
inositol
triphosphate
binding
calcium
release
Prior art date
Application number
PCT/US1993/008168
Other languages
English (en)
Inventor
Kenneth A. Stauderman
Original Assignee
Merrell Dow Pharmaceuticals 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 Merrell Dow Pharmaceuticals Inc. filed Critical Merrell Dow Pharmaceuticals Inc.
Priority to KR1019950701166A priority Critical patent/KR950703347A/ko
Priority to AU48417/93A priority patent/AU670962B2/en
Priority to EP93921252A priority patent/EP0661982A1/fr
Priority to JP6509054A priority patent/JPH08502068A/ja
Publication of WO1994007507A1 publication Critical patent/WO1994007507A1/fr
Priority to NO951163A priority patent/NO951163L/no

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/795—Polymers containing sulfur
    • 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

Definitions

  • This application relates to a series of diamino benzenedisulfonic acid oligomers that have demonstrated an affinity for the receptor sites of inositol 1,4,5- triphosphate (IP 3 ) and are, therefore useful in diminishing the bioactivity of IP 3 , especially with regard to its effect on the release of intracellular calcium ions.
  • IP 3 inositol 1,4,5- triphosphate
  • IP 3 inositol 1,4,5-triphosphate
  • Inositol 1,4,5-triphosphate IP 3
  • IP 3 acts to stimulate the release of calcium ions from storage organelles within
  • IP 3 is characterized as a "second messenger".
  • the calcium released by IP 3 functions to stimulate a variety of physiologic processes such as smooth muscle contraction, histamine secretion and the hyperpolarization of nerve
  • Any compound or agent that can promote or interfere with the function of IP 3 will promote or interfere with the generation of calcium ions and thereby elicit predictable pharmacological effects.
  • IP 3 releases calcium ions begins with the binding of IP 3 to a specific receptor protein located on an intracellular calcium storage compartment located typically on the endoplasmic reticulum. This receptor protein has been cloned and has been shown to form
  • IP 3 binds with its receptor, a calcium channel is opened causing the release of calcium stored in the cell's endoplasmic reticulum. In turn, the released calcium will elicit the appropriate cellular response.
  • the diamino benzenedisulfonic acid oligomers of this invention also appear to antagonize the effects of IP 3 by competing for the receptor site. In most cases, these compounds are more effective than heparin and demonstrate fewer secondary effects.
  • these compounds are more effective than heparin and demonstrate fewer secondary effects.
  • the oligomers of this invention would also be administered to modulate IP 3 -induced calcium release and have a salutary effect on any number of disorders that are caused or exacerbated by an inordinately productive IP 3 second messenger pathway.
  • Specific binding was defined as the difference between total binding (radioactivity in the absence of test compound and cold IP 3 ) and non-specific binding
  • the y-axis represents the concentration of free calcium ions in arbitrary units.
  • the tracing shows that two successive additions of 0.1 ⁇ M of IP 3 stimulated similar amounts of calcium ion release from cerebellar microsomes.
  • the addition of 1 ⁇ M of MDL 102,869 stimulated a small increase of calcium ion for unknown reasons.
  • calcium ion release stimulated by 0.1 ⁇ M of IP 3 was inhibited by 42%. This inhibition was overcome by the addition of 1 ⁇ M of IP 3 , consistent with competitive antagonism by MDL 102,869.
  • n is a whole number within the range of 5-20 and the pharmaceutically acceptable salts thereof.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Polyurethanes Or Polyureas (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

Des oligomères de la formule (I) se sont avérés être des antagonistes efficaces de l'inositol 1,4,5-triphosphate (IP3) en rivalisant de manière efficace avec l'IP3 sur les sites de liaison. En inhibant de façon efficace l'activité de l'IP3, les oligomères de cette invention peuvent moduler la libération du calcium intracellulaire et déclencher les effets psychologiques qui en résultent.
PCT/US1993/008168 1992-09-28 1993-08-30 Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate WO1994007507A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1019950701166A KR950703347A (ko) 1992-09-28 1993-08-30 이노시톨 1,4,5-트리포스페이트의 길항 방법(Method for Antagonizing Inositol 1,4,5-Triphosphate)
AU48417/93A AU670962B2 (en) 1992-09-28 1993-08-30 Method for antagonizing inositol 1,4,5-triphosphate
EP93921252A EP0661982A1 (fr) 1992-09-28 1993-08-30 Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate
JP6509054A JPH08502068A (ja) 1992-09-28 1993-08-30 イノシトール１，４，５‐トリスホスフェートを拮抗する方法
NO951163A NO951163L (no) 1992-09-28 1995-03-27 Metode for antagonisering av inositol-1,4,5-trifosfat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95239392A 1992-09-28 1992-09-28
US07/952,393 1992-09-28

Publications (1)

Publication Number Publication Date
WO1994007507A1 true WO1994007507A1 (fr) 1994-04-14

Family

ID=25492868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/008168 WO1994007507A1 (fr) 1992-09-28 1993-08-30 Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate

Country Status (13)

Country Link
EP (1) EP0661982A1 (fr)
JP (1) JPH08502068A (fr)
KR (1) KR950703347A (fr)
AU (1) AU670962B2 (fr)
CA (1) CA2145681A1 (fr)
HU (1) HUT70192A (fr)
IL (1) IL107066A (fr)
MX (1) MX9305933A (fr)
NO (1) NO951163L (fr)
NZ (1) NZ256178A (fr)
TW (1) TW260663B (fr)
WO (1) WO1994007507A1 (fr)
ZA (1) ZA936978B (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000586A3 (fr) * 1994-06-30 1996-02-15 Max Planck Gesellschaft Methodes de traitement d'affections a proliferation cellulaire par modulation de la transduction du signal
WO1997022251A1 (fr) * 1995-12-21 1997-06-26 Ayurcore, Inc. Compositions pour moduler la concentration de triphosphate d'inositol intracellulaire et utilisations de ces dernieres
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
US5886044A (en) * 1995-02-17 1999-03-23 Smithkline Beecham Corporation IL-8 receptor antagonists
US6005008A (en) * 1996-02-16 1999-12-21 Smithkline Beecham Corporation IL-8 receptor antagonists
US6133319A (en) * 1996-06-27 2000-10-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6211373B1 (en) 1996-03-20 2001-04-03 Smithkline Beecham Corporation Phenyl urea antagonists of the IL-8 receptor
US6262113B1 (en) 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6271261B1 (en) 1996-06-27 2001-08-07 Smithkline Beecham Corporation IL-8 receptor antagonists
WO2002038140A3 (fr) * 2000-11-09 2003-03-13 Contrimmune Biotechnology Inc Utilisations therapeutiques de modulateurs du canal calcique induits par le recepteur ip¿3?
US9771430B2 (en) 2011-09-02 2017-09-26 The Trustees Of Columbia University In The City Of New York Method of treating a metabolic disorder induced by obesity in a subject in need thereof by administering MK2/3 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB781479A (en) * 1953-08-27 1957-08-21 Ciba Ltd New polyureas and process for making them
EP0467185A2 (fr) * 1990-07-09 1992-01-22 The Dow Chemical Company Oligomères, leurs applications et formulations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB781479A (en) * 1953-08-27 1957-08-21 Ciba Ltd New polyureas and process for making them
EP0467185A2 (fr) * 1990-07-09 1992-01-22 The Dow Chemical Company Oligomères, leurs applications et formulations

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
F. O'ROURKE ET AL.: "THE INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR BINDING SITES OF PLATELET MEMBRANES", THE BIOCHEMICAL JOURNAL, vol. 267, no. 2, 1990, pages 297 - 302 *
M.A. TONES ET AL.: "THE EFFECT OF HEPARIN ON THE INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR IN RAT LIVER MICROSOMES", FEBS LETTERS, vol. 252, no. 1,2, 1989, pages 105 - 108, XP025605443, DOI: doi:10.1016/0014-5793(89)80898-1 *
See also references of EP0661982A1 *
T.K. GHOSH ET AL.: "COMPETITIVE, REVERSIBLE, AND POTENT ANTAGONISM OF INOSITOL 1,4,5-TRISPHOSPHATE-ACTIVATED CALCIUM RELEASE BY HEPARIN", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 263, no. 23, 1988, pages 11075 - 11079 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000586A3 (fr) * 1994-06-30 1996-02-15 Max Planck Gesellschaft Methodes de traitement d'affections a proliferation cellulaire par modulation de la transduction du signal
US6180675B1 (en) 1995-02-17 2001-01-30 Smithkline Beecham Corporation IL-8 receptor antagonists
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
US5886044A (en) * 1995-02-17 1999-03-23 Smithkline Beecham Corporation IL-8 receptor antagonists
WO1997022251A1 (fr) * 1995-12-21 1997-06-26 Ayurcore, Inc. Compositions pour moduler la concentration de triphosphate d'inositol intracellulaire et utilisations de ces dernieres
US6083920A (en) * 1995-12-21 2000-07-04 Ayurcore, Inc. Compositions for modulating intracellular inositol trisphosphate concentration
US6005008A (en) * 1996-02-16 1999-12-21 Smithkline Beecham Corporation IL-8 receptor antagonists
US6262113B1 (en) 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6211373B1 (en) 1996-03-20 2001-04-03 Smithkline Beecham Corporation Phenyl urea antagonists of the IL-8 receptor
US6133319A (en) * 1996-06-27 2000-10-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6271261B1 (en) 1996-06-27 2001-08-07 Smithkline Beecham Corporation IL-8 receptor antagonists
WO2002038140A3 (fr) * 2000-11-09 2003-03-13 Contrimmune Biotechnology Inc Utilisations therapeutiques de modulateurs du canal calcique induits par le recepteur ip¿3?
US9771430B2 (en) 2011-09-02 2017-09-26 The Trustees Of Columbia University In The City Of New York Method of treating a metabolic disorder induced by obesity in a subject in need thereof by administering MK2/3 inhibitors

Also Published As

Publication number Publication date
IL107066A (en) 1998-01-04
NO951163D0 (no) 1995-03-27
HUT70192A (en) 1995-09-28
IL107066A0 (en) 1993-12-28
KR950703347A (ko) 1995-09-20
AU670962B2 (en) 1996-08-08
EP0661982A1 (fr) 1995-07-12
CA2145681A1 (fr) 1994-04-14
NO951163L (no) 1995-03-27
JPH08502068A (ja) 1996-03-05
MX9305933A (es) 1994-04-29
HU9500891D0 (en) 1995-05-29
TW260663B (fr) 1995-10-21
AU4841793A (en) 1994-04-26
NZ256178A (en) 1997-03-24
ZA936978B (en) 1994-04-18

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