EP0661982A1 - Method for antagonizing inositol 1,4,5-triphosphate - Google Patents
Method for antagonizing inositol 1,4,5-triphosphateInfo
- 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
Links
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims description 9
- 230000003042 antagnostic effect Effects 0.000 title description 2
- 230000000694 effects Effects 0.000 claims abstract description 7
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 3
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims 1
- 229960000367 inositol Drugs 0.000 claims 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims 1
- 230000027455 binding Effects 0.000 abstract description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 7
- 229910052791 calcium Inorganic materials 0.000 abstract description 7
- 239000011575 calcium Substances 0.000 abstract description 7
- 239000005557 antagonist Substances 0.000 abstract description 3
- 230000003834 intracellular effect Effects 0.000 abstract description 3
- 230000001766 physiological effect Effects 0.000 abstract 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 11
- 229910001424 calcium ion Inorganic materials 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 239000000872 buffer Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- MFINAYNMQPYYKN-UHFFFAOYSA-N 3,4-diaminobenzene-1,2-disulfonic acid Chemical class NC1=CC=C(S(O)(=O)=O)C(S(O)(=O)=O)=C1N MFINAYNMQPYYKN-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000036515 potency Effects 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 206010001513 AIDS related complex Diseases 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241001492222 Epicoccum Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 108091008585 IP3 receptors Proteins 0.000 description 1
- 102000007640 Inositol 1,4,5-Trisphosphate Receptors Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000037037 animal physiology Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012134 supernatant fraction Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (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)
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 (en) | 1992-09-28 | 1993-08-30 | Method for antagonizing inositol 1,4,5-triphosphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0661982A1 true EP0661982A1 (en) | 1995-07-12 |
Family
ID=25492868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93921252A Ceased EP0661982A1 (en) | 1992-09-28 | 1993-08-30 | Method for antagonizing inositol 1,4,5-triphosphate |
Country Status (13)
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996000586A2 (en) * | 1994-06-30 | 1996-01-11 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Methods for treating cell proliferative disorders by modulating signal transduction |
| US5780483A (en) * | 1995-02-17 | 1998-07-14 | Smithkline Beecham Corporation | IL-8 receptor antagonists |
| JPH11503110A (ja) * | 1995-02-17 | 1999-03-23 | スミスクライン・ビーチャム・コーポレイション | Ｉｌ−８受容体拮抗剤 |
| 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 |
| PL330849A1 (en) | 1996-06-27 | 1999-06-07 | Smithkline Beecham Corp | Antagonists of il-8 receptors |
| CZ425598A3 (cs) * | 1996-06-27 | 1999-08-11 | Smithkline Beecham Corporation | Antagonista IL-8 receptoru |
| WO2002038140A2 (en) * | 2000-11-09 | 2002-05-16 | Contrimmune Biotechnology Inc | Therapeutic uses for ip3 receptor-mediated calcium channel modulators |
| BR112014005104A2 (pt) | 2011-09-02 | 2017-07-04 | Salk Inst For Biological Studi | inibidores camkii, ip3r, calcineurin, p38 e mk2/3 para tratar atar distúrbios metabólicos de obesidade |
Family Cites Families (2)
| 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 |
-
1993
- 1993-08-30 CA CA002145681A patent/CA2145681A1/en not_active Abandoned
- 1993-08-30 KR KR1019950701166A patent/KR950703347A/ko not_active Ceased
- 1993-08-30 AU AU48417/93A patent/AU670962B2/en not_active Ceased
- 1993-08-30 EP EP93921252A patent/EP0661982A1/en not_active Ceased
- 1993-08-30 HU HU9500891A patent/HUT70192A/hu unknown
- 1993-08-30 JP JP6509054A patent/JPH08502068A/ja active Pending
- 1993-08-30 WO PCT/US1993/008168 patent/WO1994007507A1/en not_active Application Discontinuation
- 1993-08-30 NZ NZ256178A patent/NZ256178A/en unknown
- 1993-09-21 ZA ZA936978A patent/ZA936978B/xx unknown
- 1993-09-22 IL IL107066A patent/IL107066A/en not_active IP Right Cessation
- 1993-09-22 TW TW082107787A patent/TW260663B/zh active
- 1993-09-27 MX MX9305933A patent/MX9305933A/es unknown
-
1995
- 1995-03-27 NO NO951163A patent/NO951163D0/no unknown
Non-Patent Citations (1)
| 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 |
| TW260663B (enrdf_load_stackoverflow) | 1995-10-21 |
| NO951163L (no) | 1995-03-27 |
| ZA936978B (en) | 1994-04-18 |
| WO1994007507A1 (en) | 1994-04-14 |
| IL107066A0 (en) | 1993-12-28 |
| JPH08502068A (ja) | 1996-03-05 |
| MX9305933A (es) | 1994-04-29 |
| AU670962B2 (en) | 1996-08-08 |
| CA2145681A1 (en) | 1994-04-14 |
| IL107066A (en) | 1998-01-04 |
| AU4841793A (en) | 1994-04-26 |
| HUT70192A (en) | 1995-09-28 |
| KR950703347A (ko) | 1995-09-20 |
| NZ256178A (en) | 1997-03-24 |
| NO951163D0 (no) | 1995-03-27 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19950330 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE |
|
| 17Q | First examination report despatched |
Effective date: 19951009 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
|
| 18R | Application refused |
Effective date: 19960331 |