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Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 2
1Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd., Shizuoka-ken, Japan.
Journal of Medicinal Chemistry
|September 4, 1992
Summary
Researchers developed potent thromboxane A2/prostaglandin H2 receptor antagonists. Compound 57 (KW-3635) shows high affinity for human receptors and inhibits platelet aggregation, advancing to clinical trials.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cardiovascular Research
Background:
- Thromboxane A2 (TXA2) and Prostaglandin H2 (PGH2) receptors play crucial roles in platelet aggregation and cardiovascular function.
- Development of selective antagonists for these receptors is a key therapeutic strategy for cardiovascular diseases.
Purpose of the Study:
- To synthesize and evaluate novel dibenz[b,e]oxepin derivatives as TXA2/PGH2 receptor antagonists.
- To identify key structural features responsible for high receptor affinity and antagonist activity.
- To assess the in vitro and ex vivo efficacy of lead compounds in inhibiting platelet aggregation.
Main Methods:
- Synthesis of a series of 11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives.
- Radioligand binding assays using [3H]U-46619 to determine TXA2/PGH2 receptor antagonist affinity in guinea pig and human platelets.
- Structure-activity relationship (SAR) analysis to identify optimal structural modifications.
- In vitro and ex vivo platelet aggregation assays using U-46619 as the agonist.
Main Results:
- Key structural requirements for potent TXA2/PGH2 receptor antagonism include an (E)-2-(1-benzimidazolyl)ethylidene side chain at the 11-position and a carboxyl group at the 2-position of the dibenzoxepin ring.
- Receptor binding affinities in guinea pig platelets did not strongly correlate with those in human platelets.
- Sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monohydrate (Compound 57, KW-3635) exhibited the highest affinity for the human TXA2/PGH2 receptor (Ki = 1.2 ± 0.14 nM).
- Compound 57 demonstrated potent inhibition of U-46619-induced platelet aggregation in both guinea pig and human platelets.
- KW-3635 is an orally active, specific TXA2/PGH2 receptor antagonist without agonistic or TXA2 synthase inhibitory effects.
Conclusions:
- Novel dibenz[b,e]oxepin derivatives are effective TXA2/PGH2 receptor antagonists.
- Compound 57 (KW-3635) is a highly potent and selective human TXA2/PGH2 receptor antagonist with promising antiplatelet activity.
- KW-3635 is currently under clinical evaluation for potential therapeutic applications.