title: 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.
abstract: 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 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 +/- 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.
authors.affiliation: Natural and Synthetic Drug Research Center, University of Liège, Belgium. Jean-Michel.Dogne@ulg.ac.be
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.forename: Xavier
authors.initials: X
authors.lastname: de Leval
authors.forename: Philippe
authors.initials: P
authors.lastname: Kolh
authors.forename: Vincent
authors.initials: V
authors.lastname: Tchana-Sato
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rolin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ghuysen
authors.forename: Patrick
authors.initials: P
authors.lastname: Segers
authors.forename: Bernard
authors.initials: B
authors.lastname: Lambermont
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001786:Blood Glucose / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D004232:Diuretics; C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013453:Sulfonylurea Compounds; D013930:Thromboxane-A Synthase