title: Effects of a novel non-carboxylic thromboxane A2 receptor antagonist (BM-531) derived from torasemide on platelet function.
abstract: In this study we examined the thromboxane A(2)(TXA(2)) receptor antagonist property of BM-531 (N-tert -butyl- N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, on platelet function. The drug affinity for human washed platelet TXA(2)receptors labelled with [(3)H]SQ-29,548 has been determined (IC50: 0.0078 microM) and demonstrated to be higher than sulotroban (IC50: 0.93 microM) and SQ-29,548 (IC50: 0.021 microM). The antiaggregatory potency has been confirmed since we demonstrated that BM-531 prevented platelet aggregation in human citrated platelet-rich plasma induced by arachidonic acid (600 microM) (ED100: 0.125 microM), U-46619, a stable TXA(2)agonist (1 microM) (ED50: 0.482 microM) and collagen (1 microg mL(-1)) (% of inhibition: 42.9% at 10 microM) and inhibited the second wave of ADP (2 microM). Moreover, when BM-531 was incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA-100(trade mark)) was significantly prolonged. These results suggest that BM-531 can be regarded as a novel non-carboxylic TXA(2)antagonist with a powerful antiplatelet potency.
authors.affiliation: Department of Medicinal Chemistry, University of Liège, Belgium. jean-michel.dogne@ulg.ac.be
authors.forename: J M
authors.initials: JM
authors.lastname: Dogné
authors.forename: X
authors.initials: X
authors.lastname: de Leval
authors.forename: P
authors.initials: P
authors.lastname: Neven
authors.forename: S
authors.initials: S
authors.lastname: Rolin
authors.forename: J
authors.initials: J
authors.lastname: Wauters
authors.forename: J L
authors.initials: JL
authors.lastname: David
authors.forename: J
authors.initials: J
authors.lastname: Delarge
authors.forename: B
authors.initials: B
authors.lastname: Massereel
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013997:Time Factors; D000077786:Torsemide
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; C412612:BM 531; D000244:Adenosine Diphosphate; C040624:sulotroban; C045749:SQ 29548; D000077786:Torsemide