title: In vitro antiplatelet profiles of the new thromboxane synthetase inhibitor sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate.
abstract: The in vitro properties of CS-518 (RS-5186; sodium 2-(1-imidazolylmethyl)- 4,5-dihydrobenzo[b]thiophene-6-carboxylate, CAS 113817-57-5), a new thromboxane (TX) synthetase inhibitor, as an antiplatelet agent were investigated. Incubation of clotting whole blood from man, rabbits, and dogs with CS-518 resulted in a concentration-dependent reduction of TXB2 production and an increase in 6-keto-PGF1 alpha. Similar properties were also observed for ozagrel and isbogrel, but both agents were less effective on TXB2 production. CS-518 inhibited arachidonic acid (AA)- or collagen-induced platelet aggregation in platelet rich plasma (PRP) from man, rabbits and dogs. In addition, antiaggregatory effects of CS-518 were confirmed in whole blood by two methods: impedance method and free platelet count method. TXA2 formation in washed canine platelets in response to AA (0.1 mmol/l) was dose-dependently inhibited by incubation with CS-518. This inhibition by CS-518 was gradually attenuated after platelets were subsequently washed with drug-free buffer, but a dose-dependent inhibition was still observed with platelets that had been washed three times. Ozagrel also inhibited TXB2 formation when incubated with platelets, whereas this inhibition disappeared with platelets only washed once. In contrast, platelets treated with acetylsalicylic acid, an irreversible inhibitor of cyclooxygenase showed a comparable inhibition before and after they were washed three times. These results indicate that CS-518 exerts antiplatelet effects in vitro via potent, selective, and long-lasting but reversible inhibition on TX synthetase.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Asai
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Ushiyama
authors.forename: K
authors.initials: K
authors.lastname: Matsuda
authors.forename: T
authors.initials: T
authors.lastname: Oshima
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000378:metabolism; D000328:Adult; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D011817:Rabbits; D013876:Thiophenes / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000032:analysis / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000096:biosynthesis / Q000097:blood
chemical_list: D007093:Imidazoles; D008689:Methacrylates; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D013931:Thromboxanes; C029166:dazoxiben; C055806:RS 5186; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; C034364:ozagrel; D001241:Aspirin