ASP6537, a novel highly selective cyclooxygenase-1 inhibitor, exerts potent antithrombotic effect without "aspirin dilemma"

作者：Sakata Chinatsu^*; Kawasaki Tomihisa; Kato Yasuko; Abe Masaki; Suzuki Ken ichi; Ohmiya Makoto; Funatsu Toshiyuki; Morita Yoshiaki; Okada Masamichi

来源：Thrombosis Research, 2013, 132(1): 56-62.

DOI：10.1016/j.thromres.2013.03.005

• Cyclooxygenase
• Platelet
• Thromboxane A(2)
• Prostaglandin I-2
• Aspirin
• Thrombosis

Introduction: Aspirin inhibits both the cyclooxygenase (COX)-1-dependent production of thromboxane A(2) (TXA(2)) in platelets and COX-2-dependent production of anti-aggregatory prostaglandin I-2 (PGI(2)) in vessel walls, resulting in "aspirin dilemma." Our objective is to investigate whether ASP6537 can overcome aspirin dilemma and exert a potent antithrombotic effect without a concurrent ulcerogenic effect. Methods: We evaluated the inhibitory effects of ASP6537 on recombinant human COX-1 (rhCOX-1) and rhCOX-2 activities using a COX-1/2 selectivity test. To determine whether ASP6537 induces aspirin dilemma, we examined the effects of ASP6537 on in vitro TXA(2) and PGI(2) metabolite production from platelets and isolated aorta of guinea pigs, and on plasma concentrations of TXA(2) and PGI(2) metabolites in aged rats. Finally, we evaluated the antithrombotic effects and ulcerogenic activity of ASP6537 using an electrically induced carotid arterial thrombosis model and a gastric ulcer model in guinea pigs. Results: The IC50 ratios of rhCOX-2 to rhCOX-1 for ASP6537 and aspirin were > 142,000 and 1.63 fold, respectively. ASP6537 inhibited TXA(2) production more selectively than aspirin in in vitro and in vivo TXA(2)/PGI(2) production studies. ASP6537 exerted a significant antithrombotic effect at >= 3 mg/kg, while aspirin tended to inhibit thrombosis at 300 mg/kg but it was not statistically significant. Further, ASP6537 did not induce ulcer formation at 100 mg/kg, whereas aspirin exhibited an ulcerogenic effect at doses of >= 100 mg/kg. Conclusions: ASP6537 functions as a highly selective COX-1 inhibitor with a superior ability to aspirin for normalizing TXA(2)/PGI(2) balance, and exerts antithrombotic effect without ulcerogenic effect.

• 出版日期2013-7