Pharmacological Characterization of N-tert-Butyl-NЈ-[2-(4Ј- methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A 2 Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bl

ABSTRACT The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-NЈ-[2-(4Ј-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F 2 )-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 Ϯ 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 Ϯ 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia. The isozymes cyclooxygenase (COX)-1 and -2 catalyze the conversion of arachidonic acid into thromboxane A 2 (TXA 2 ) and prostaglandins (PGs). The eicosanoid TXA 2 is the major COX-1 product of arachidonic acid metabolism in platelets