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±0.1 nM) for the TP receptors in comparison with BM-531 (IC 50: 7.8±0.7 nM) and sulotroban (IC 50: 931±85 nM), two TXA 2 antagonists. We also demonstrated that BM-567 prevented platelet aggregation induced by arachidonic acid (AA) (600 μM) (ED 100: 0.20±0.10 μM), U-46619, a stable TXA 2 agonist (1 μM) (ED 50: 0.30±0.04 μM) and collagen (1 μg ml -1) (% of inhibition: 44.3±4.3% at 10 μM) and inhibited the second wave of ADP (2 μM). Moreover, when BM-567 was incubated in whole blood from healthy donors, the closure time measured by the Platelet Function analyzer (PFA-100®) was significantly prolonged (closure time: 215±21 s) by using collagen/epinephrine cartridges. Finally, at the concentration of 1 μM, BM-567 completely reduced the TXB 2 production from human platelets stimulated with AA (600 μM). These results indicate that BM-567 is a novel combined TXA 2 receptor antagonist and thromboxane synthase inhibitor characterized by a powerful antiplatelet potency.
|Titolo:||Pharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function.|
|Data di pubblicazione:||2003|
|Appare nelle tipologie:||1.1 Articolo in rivista|