title: Pharmacological profile and therapeutic potential of BM-573, a combined thromboxane receptor antagonist and synthase inhibitor.
abstract: BM-573 (N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea), a torsemide derivative, is a novel non-carboxylic dual TXA2 synthase inhibitor and receptor antagonist. The pharmacological profile of the drug is characterized by a higher affinity for the thromboxane receptor than that of SQ-29548, one of the most powerful antagonists described to date, by a complete prevention of human platelet aggregation induced by arachidonic acid at a lower dose than either torsemide or sulotroban, and by a significantly prolonged closure time measured by the platelet function analyser (PFA-100). Moreover, at the concentrations of 1 and 10 microM, BM-573 completely prevented production of TXB2 by human platelets activated by 0.6 mM of arachidonic acid. BM-573 prevents rat fundus contraction induced by U-46619 but not by prostacyclin or other prostaglandins. Despite possessing a chemical structure very similar to that of a diuretic torsemide, BM-573 has no diuretic activity. BM-573 does not prolong bleeding time and, unlike some of the other sulfonylureas, has no effect on blood glucose levels. In vivo, BM-573 appears to have antiplatelet and antithrombotic activities since it reduced thrombus weight and prolonged the time to abdominal aorta occlusion induced by ferric chloride. BM-573 also relaxed rat aorta and guinea pig trachea precontracted with U-46619. In pigs, BM-573 completely antagonized pulmonary hypertensive effects of U-46619 and reduced the early phase of pulmonary hypertension in models of endotoxic shock and pulmonary embolism. Finally, BM-573 protected pigs from myocardial infarction induced by coronary thrombosis. These results suggest that BM-573 should be viewed as a promising therapeutic agent in the treatment of pulmonary hypertension and syndromes associated with platelet activation.
authors.affiliation: Hemodynamics Research Laboratory (Hemoliège), University of Liège, Liège, Belgium. a.ghuysen@chu.ulg.ac.be
authors.forename: Alexandre
authors.initials: A
authors.lastname: Ghuysen
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Patrice
authors.initials: P
authors.lastname: Chiap
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rolin
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Bernard
authors.initials: B
authors.lastname: Lambermont
authors.forename: Philippe
authors.initials: P
authors.lastname: Kolh
authors.forename: Vincent
authors.initials: V
authors.lastname: Tchana-Sato
authors.forename: Julien
authors.initials: J
authors.lastname: Hanson
authors.forename: Vincent
authors.initials: V
authors.lastname: D'Orio
mesh_terms: D000818:Animals; D006801:Humans; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D013930:Thromboxane-A Synthase