EP0661982A1 - 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

Info

Publication number
EP0661982A1
EP0661982A1 EP93921252A EP93921252A EP0661982A1 EP 0661982 A1 EP0661982 A1 EP 0661982A1 EP 93921252 A EP93921252 A EP 93921252A EP 93921252 A EP93921252 A EP 93921252A EP 0661982 A1 EP0661982 A1 EP 0661982A1
Authority
EP
European Patent Office
Prior art keywords
inositol
triphosphate
binding
calcium
release
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP93921252A
Other languages
German (de)
English (en)
Inventor
Kenneth A. Stauderman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharmaceuticals Inc
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
Publication of EP0661982A1 publication Critical patent/EP0661982A1/fr
Ceased legal-status Critical Current

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.

Landscapes

  • 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.
EP93921252A 1992-09-28 1993-08-30 Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate Ceased EP0661982A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US95239392A 1992-09-28 1992-09-28
US952393 1992-09-28
PCT/US1993/008168 WO1994007507A1 (fr) 1992-09-28 1993-08-30 Procede d'inhibition de l'activite de l'inositol 1,4,5-triphosphate

Publications (1)

Publication Number Publication Date
EP0661982A1 true EP0661982A1 (fr) 1995-07-12

Family

ID=25492868

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93921252A Ceased EP0661982A1 (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)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000586A2 (fr) * 1994-06-30 1996-01-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Methodes de traitement d'affections a proliferation cellulaire par modulation de la transduction du signal
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
EP0809492A4 (fr) * 1995-02-17 2007-01-24 Smithkline Beecham Corp Antagonistes des recepteurs d'il-8
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
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
JP2000514049A (ja) * 1996-06-27 2000-10-24 スミスクライン・ビーチャム・コーポレイション Ｉｌ―８受容体拮抗薬
CZ425698A3 (cs) 1996-06-27 1999-06-16 Smithkline Beecham Corporation Antagonista IL-8 receptoru
AU2002214886A1 (en) * 2000-11-09 2002-05-21 Contrimmune Biotechnology Inc Therapeutic uses for IP3 receptor-mediated calcium channel modulators
CA2857374A1 (fr) 2011-09-02 2013-03-07 The Trustees Of Columbia University In The City Of New York Inhibiteurs de camkii, ip3r, calcineurine, p38 et mk2/3 pour traiter des perturbations metaboliques de l'obesite

Family Cites Families (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
US5276182A (en) * 1990-07-09 1994-01-04 The Dow Chemical Company Process for preparing polyurea oligomers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FEBS LETTERS, vol. 252, no. 1,2, 1989, pages 105-108; M.A. TONES ET AL.: 'THE EFFECT OF HEPARIN ON THE INOSITOL 1,4,5-TRISHOSPHATE RECEPTOR IN RAT LIVER NICROSOMES' *

Also Published As

Publication number Publication date
HU9500891D0 (en) 1995-05-29
IL107066A (en) 1998-01-04
MX9305933A (es) 1994-04-29
NO951163D0 (no) 1995-03-27
AU4841793A (en) 1994-04-26
AU670962B2 (en) 1996-08-08
KR950703347A (ko) 1995-09-20
WO1994007507A1 (fr) 1994-04-14
ZA936978B (en) 1994-04-18
NZ256178A (en) 1997-03-24
TW260663B (fr) 1995-10-21
CA2145681A1 (fr) 1994-04-14
JPH08502068A (ja) 1996-03-05
NO951163L (no) 1995-03-27
IL107066A0 (en) 1993-12-28
HUT70192A (en) 1995-09-28

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