title: Pharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function.
abstract: The aim of this work was to evaluate the effects of BM-567 (N-pentyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, on both thromboxane A(2) (TXA(2)) receptors (TP) and thromboxane synthase of human platelets. The drug affinity for TP receptors of human washed platelets has been determined. In this test, BM-567 showed a high affinity (IC(50): 1.1+/-0.1nM) for the TP receptors in comparison with BM-531 (IC(50): 7.8+/-0.7nM) and sulotroban (IC(50): 931+/-85nM), two TXA(2) antagonists. We also demonstrated that BM-567 prevented platelet aggregation induced by arachidonic acid (AA) (600 microM) (ED(100): 0.20+/-0.10 microM), U-46619, a stable TXA(2) agonist (1 microM) (ED(50): 0.30+/-0.04 microM) and collagen (1microgram ml(-1)) (% of inhibition: 44.3+/-4.3% at 10 microM) and inhibited the second wave of ADP (2microM). Moreover, when BM-567 was incubated in whole blood from healthy donors, the closure time measured by the Platelet Function analyzer (PFA-100((R))) was significantly prolonged (closure time: 215+/-21s) by using collagen/epinephrine cartridges. Finally, at the concentration of 1 microM, BM-567 completely reduced the TXB(2) production from human platelets stimulated with AA (600 microM). These results indicate that BM-567 is a novel combined TXA(2) receptor antagonist and thromboxane synthase inhibitor characterized by a powerful antiplatelet potency.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Medicinal Chemistry, Natural and Synthetic Drugs Research Center, University of Liège, 1, avenue de l'Hôpital, Liège, Belgium. jean-michele.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: Kolh
authors.forename: V
authors.initials: V
authors.lastname: Sanna
authors.forename: S
authors.initials: S
authors.lastname: Rolin
authors.forename: C
authors.initials: C
authors.lastname: Michaux
authors.forename: M
authors.initials: M
authors.lastname: Mauer
authors.forename: J L
authors.initials: JL
authors.lastname: David
authors.forename: B
authors.initials: B
authors.lastname: Masereel
authors.forename: B
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000378:metabolism*
chemical_list: C434802:BM 567; D010975:Platelet Aggregation Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013453:Sulfonylurea Compounds; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase