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

Abstract 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 IC 50 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.