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Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-21 , DOI: 10.1021/acs.jmedchem.2c00359 E Scott Priestley 1 , Jacques Banville 2 , Daniel Deon 2 , Laurence Dubé 2 , Marc Gagnon 2 , Julia Guy 2 , Philippe Lapointe 2 , Jean-François Lavallée 2 , Alain Martel 2 , Serge Plamondon 2 , Roger Rémillard 2 , Edward Ruediger 2 , François Tremblay 2 , Shana L Posy 1 , Victor R Guarino 1 , Jeremy M Richter 1 , Jianqing Li 1 , Anuradha Gupta 3 , Muthalagu Vetrichelvan 3 , T J Balapragalathan 3 , Arvind Mathur 1 , Ji Hua 1 , Mario Callejo 2 , Jocelyne Guay 2 , Chi Shing Sum 1 , Mary Ellen Cvijic 1 , Carol Watson 1 , Pancras Wong 1 , Jing Yang 1 , Michel Bouvier 2, 4 , David A Gordon 1 , Ruth R Wexler 1 , Anne Marinier 2, 5
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-21 , DOI: 10.1021/acs.jmedchem.2c00359 E Scott Priestley 1 , Jacques Banville 2 , Daniel Deon 2 , Laurence Dubé 2 , Marc Gagnon 2 , Julia Guy 2 , Philippe Lapointe 2 , Jean-François Lavallée 2 , Alain Martel 2 , Serge Plamondon 2 , Roger Rémillard 2 , Edward Ruediger 2 , François Tremblay 2 , Shana L Posy 1 , Victor R Guarino 1 , Jeremy M Richter 1 , Jianqing Li 1 , Anuradha Gupta 3 , Muthalagu Vetrichelvan 3 , T J Balapragalathan 3 , Arvind Mathur 1 , Ji Hua 1 , Mario Callejo 2 , Jocelyne Guay 2 , Chi Shing Sum 1 , Mary Ellen Cvijic 1 , Carol Watson 1 , Pancras Wong 1 , Jing Yang 1 , Michel Bouvier 2, 4 , David A Gordon 1 , Ruth R Wexler 1 , Anne Marinier 2, 5
Affiliation
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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 (43), and a backup clinical candidate, BMS-986141 (49). 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.
中文翻译：
发现两种拮抗蛋白酶激活受体 4 的新型抗血小板临床候选药物（BMS-986120 和 BMS-986141）
蛋白酶激活受体 4 (PAR4) 是一种 G 蛋白偶联受体，在人血小板上表达并被凝血酶凝血酶激活。PAR4在凝血中起关键作用，近年来其在病理性血栓形成中的重要性日益得到认可。在此，我们描述了一系列咪唑噻二唑 PAR4 拮抗剂对一流临床候选药物 BMS-986120 ( 43 ) 和备用临床候选药物 BMS-986141 ( 49 ) 的优化。与临床上重要的抗血小板药物氯吡格雷相比，这两种化合物在猴模型中表现出优异的抗血栓形成功效和最小的出血时间延长，并为提高动脉血栓形成治疗的护理标准提供了潜在机会。
更新日期：2022-06-21
中文翻译：
发现两种拮抗蛋白酶激活受体 4 的新型抗血小板临床候选药物（BMS-986120 和 BMS-986141）
蛋白酶激活受体 4 (PAR4) 是一种 G 蛋白偶联受体，在人血小板上表达并被凝血酶凝血酶激活。PAR4在凝血中起关键作用，近年来其在病理性血栓形成中的重要性日益得到认可。在此，我们描述了一系列咪唑噻二唑 PAR4 拮抗剂对一流临床候选药物 BMS-986120 ( 43 ) 和备用临床候选药物 BMS-986141 ( 49 ) 的优化。与临床上重要的抗血小板药物氯吡格雷相比，这两种化合物在猴模型中表现出优异的抗血栓形成功效和最小的出血时间延长，并为提高动脉血栓形成治疗的护理标准提供了潜在机会。
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