Pharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function |
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| Authors: | Dogné J M de Leval X Kolh P Sanna V Rolin S Michaux C Mauer M David J L Masereel B Pirotte B |
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| Institution: | 1. Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA;2. Department of Biostatistics, UCLA, Los Angeles, CA 90095, USA;3. Department of Medicine, Stanford University Medical Center, Stanford, CA 94305, USA;4. Department of Surgery, Stanford University, Stanford, CA 94305, USA;5. Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;6. Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;1. Dipartimento di Studi per l’Economia e l’Impresa, Università del Piemonte Orientale, Via Perrone 18, Novara 28100, Italy;2. Cass Business School, City, University of London, 106 Bunhill Row, London EC1Y 8TZ, UK;1. University of Florence, Department of Chemistry \"Ugo Schiff\", Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy;2. University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;3. Centre of Advanced Research in Bionanoconjugates and Biopolymers Department, “Petru Poni” Institute of Macromolecular Chemistry, 700487, Iasi, Romania |
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| 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. |
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