title: Effects of KW-3635, a novel dibenzoxepin derivative of a selective thromboxane A2 antagonist, on human, guinea pig and rat platelets.
abstract: We examined the binding of [3H]U-46619, a thromboxane A2 agonist, to human and guinea pig platelets and the binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to human, rat and guinea pig platelets. KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1- benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate monohydrate) concentration-dependently inhibited the [3H]U-46619 binding to human and guinea pig platelets with inhibition constants of 1.2 nM and 2.7 nM, respectively. KW-3635 also potently inhibited the [3H]SQ 29,548 binding to human and guinea pig platelets with inhibition constants of 1.9 nM and 3.2 nM, respectively. In contrast, KW-3635 was less active against thromboxane A2/prostaglandin H2 receptors in rat platelets with an inhibition constant of 97 nM. KW-3635 at 10(-5) M did not antagonize various receptors including prostaglandin E2, prostaglandin I2 and neurotransmitters. In addition, 10(-5) M KW-3635 did not alter the prostaglandin D2-induced cAMP accumulation in EBTr cells. KW-3635 was inactive towards thromboxane synthase, cyclooxygenase and prostaglandin I2 synthase up to 10(-5) M. KW-3635 slightly inhibited 5-lipoxygenase with an IC50 value of 71 microM. These data indicate that KW-3635 is a potent and selective non-prostanoic thromboxane A2 antagonist, and it can recognize the species differences in thromboxane A2/prostaglandin H2 receptors.
authors.affiliation: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoku, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Miki
authors.forename: N
authors.initials: N
authors.lastname: Kishibayashi
authors.forename: H
authors.initials: H
authors.lastname: Nonaka
authors.forename: E
authors.initials: E
authors.lastname: Ohshima
authors.forename: H
authors.initials: H
authors.lastname: Takami
authors.forename: H
authors.initials: H
authors.lastname: Obase
authors.forename: A
authors.initials: A
authors.lastname: Ishii
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001584:Benzoxepins / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017482:Receptors, Thromboxane / Q000187:drug effects*; D013045:Species Specificity; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D014316:Tritium; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001584:Benzoxepins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D014316:Tritium; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C065729:KW 3635