Bristol-Myers Squibb Research & Early Development, 3551 Lawrenceville Road, Princeton, New Jersey08540, United States.
Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Downtown Station, Montréal, QuébecH3C 3J7, Canada.
J Med Chem. 2022 Jul 14;65(13):8843-8854. doi: 10.1021/acs.jmedchem.2c00359. Epub 2022 Jun 21.
Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (), and a backup clinical candidate, BMS-986141 (). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
蛋白酶激活受体 4 (PAR4) 是一种 G 蛋白偶联受体，在人类血小板上表达，并被凝血酶激活。PAR4 在血液凝固中起着关键作用，近年来，其在病理性血栓形成中的重要性越来越受到人们的认可。在此，我们描述了一系列咪唑并噻二唑 PAR4 拮抗剂的优化，以得到首个临床候选药物 BMS-986120（）和一个备用临床候选药物 BMS-986141（）。与临床上重要的抗血小板药物氯吡格雷相比，这两种化合物在猴子模型中均表现出优异的抗血栓形成功效和最小的出血时间延长，为改善动脉血栓形成治疗的标准护理提供了潜在机会。
