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CARDIOVASCULAR

Pharmacological Characterization of N-tert-Butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a Novel Thromboxane A₂ Receptor Antagonist and Thromboxane Synthase Inhibitor in a Rat Model of Arterial Thrombosis and Its Effects on Bleeding Time

Natural and Synthetic Drug Research Center, University of Liège, Liège, Belgium (J.-M.D., J.H., X.d.L., B.P.); Experimental Hemodynamics Laboratory (HemoLiège) (P.K., V.T.-S., A.G., B.L.) and Department of Pathology (L.d.L.), University Hospital of Liège, Liège, Belgium; Department of Pharmacy, University of Namur, Namur, Belgium (S.R., B.M.); Hydraulics Laboratory, Institute of Biomedical Technology, Ghent University, Ghent, Belgium (P.S.)

The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N'-[2-(4'-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 F₂)-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 ± 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 ± 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.

Address correspondence to: Dr. Jean-Michel Dogné, Natural and Synthetic Drug Research Center, University of Liège, Avenue de l'Hôpital, 1, B36, B-4000 Liège, Belgium. E-mail: Jean-Michel.Dogne{at}ulg.ac.be

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