Pharmacology of the thromboxane receptor antagonist and thromboxane synthase inhibitor BM-531.

J. Dogné, S. Rolin, X. de Leval, P. Benoit, P. Neven, J. Delarge, P. Kolh, J. Damas, J. David, B. Masereel
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引用次数: 27

Abstract

BM-531 (N-tert-butyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative, is a novel noncarboxylic thromboxane receptor antagonist and thromboxane synthase inhibitor. Indeed, its affinity for human washed platelet TXA2 receptors labeled with [3H]SQ-29548 (IC50 = 0.0078 microM) is higher than sulotroban (IC50 = 0.93 microM) and SQ-29548 (IC50 = 0.021 microM). Moreover, BM-531 is characterized by a potent antiaggregatory property. Indeed, on one hand, in human citrated platelet-rich plasma BM-531 prevents platelet aggregation induced by arachidonic acid (600 microM) (ED100 = 0.125 microM), U-46619, a stable TXA2 agonist (1 microM) (ED50 = 0.482 microM) or collagen (1 microgram/mL) (percentage of inhibition: 42.9% at 10 microM) and inhibits the second wave of ADP (2 microM)-induced aggregation. On the other hand, when BM-531 is incubated in whole blood from healthy donors, the closure time measured by the recently developed platelet function analyser (PFA-100) is significantly prolonged. In addition, at the concentrations of 10 and 1 microM, BM-531 totally prevents the production of TXB2 by human platelets activated by arachidonic acid. Finally, at 10 microM, BM-531 significantly prevents rat fundus contractions induced by U-46619 but not by prostacyclin. These results suggest that BM-531, which is devoid of the diuretic property of torasemide, can be regarded as a promising antiplatelet agent.
血栓素受体拮抗剂和凝血素合成酶抑制剂BM-531的药理学研究。
BM-531 (n -叔丁基-n '-[(2-环己基氨基-5-硝基苯)磺酰]尿素)是一种新型的非羧基血栓素受体拮抗剂和血栓素合成酶抑制剂。事实上,它对[3H]SQ-29548标记的人洗涤血小板TXA2受体的亲和力(IC50 = 0.0078微米)高于苏洛troban (IC50 = 0.93微米)和SQ-29548 (IC50 = 0.021微米)。此外,BM-531的特点是具有强大的抗聚集性。事实上,一方面,在人柠檬酸富含血小板的血浆中,BM-531可以阻止花生四烯酸(600微米)(ED100 = 0.125微米)、U-46619(一种稳定的TXA2激动剂(1微米)(ED50 = 0.482微米)或胶原(1微克/毫升)(10微米时抑制百分比:42.9%)诱导的血小板聚集,并抑制ADP(2微米)诱导的第二波聚集。另一方面,当BM-531在健康献血者的全血中孵育时,最近开发的血小板功能分析仪(PFA-100)测量的关闭时间显着延长。另外,在10和1 μ m浓度下,BM-531完全阻止花生四烯酸激活的人血小板产生TXB2。最后,在10微米时,BM-531对U-46619诱导的大鼠眼底收缩有明显的抑制作用,而对前列环素没有抑制作用。这些结果表明,BM-531不具有托拉塞米的利尿特性,可以作为一种有前景的抗血小板药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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