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Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-08-05 , DOI: 10.1021/acs.jmedchem.9b00186 Michael M Miller 1 , Jacques Banville 2 , Todd J Friends 1 , Mark Gagnon 2 , Jon J Hangeland 1 , Jean-François Lavallée 2 , Alain Martel 2 , Harold O'Grady 1 , Roger Rémillard 2 , Edward Ruediger 2 , François Tremblay 2 , Shana L Posy 3 , Nick J Allegretto 1 , Victor R Guarino 1 , David G Harden 4 , Timothy W Harper 1 , Karen Hartl 1 , Jonathan Josephs 1 , Sarah Malmstrom 1 , Carol Watson 1 , Yanou Yang 1 , Ge Zhang 1 , Pancras Wong 1 , Jing Yang 1 , Michel Bouvier 2, 5 , Dietmar A Seiffert 1 , Ruth R Wexler 1 , R Michael Lawrence 1 , E Scott Priestley 1 , Anne Marinier 2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-08-05 , DOI: 10.1021/acs.jmedchem.9b00186 Michael M Miller 1 , Jacques Banville 2 , Todd J Friends 1 , Mark Gagnon 2 , Jon J Hangeland 1 , Jean-François Lavallée 2 , Alain Martel 2 , Harold O'Grady 1 , Roger Rémillard 2 , Edward Ruediger 2 , François Tremblay 2 , Shana L Posy 3 , Nick J Allegretto 1 , Victor R Guarino 1 , David G Harden 4 , Timothy W Harper 1 , Karen Hartl 1 , Jonathan Josephs 1 , Sarah Malmstrom 1 , Carol Watson 1 , Yanou Yang 1 , Ge Zhang 1 , Pancras Wong 1 , Jing Yang 1 , Michel Bouvier 2, 5 , Dietmar A Seiffert 1 , Ruth R Wexler 1 , R Michael Lawrence 1 , E Scott Priestley 1 , Anne Marinier 2
Affiliation
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In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.
中文翻译：
发现具有体内抗血栓功效的强蛋白酶激活的受体4拮抗剂。
为了确定新型抗血栓形成剂，我们通过在猴子血栓形成模型中开发和评估工具化合物UDM-001651，研究了蛋白酶激活的受体4（PAR4）拮抗作用。从高通量筛选开始，我们确定了基于咪唑并噻二唑的PAR4拮抗剂化学型。详细的结构-活性关系研究能够优化有效，选择性和口服生物利用的PAR4拮抗剂UDM-001651。UDM-001651在猴子血栓形成模型中进行了评估，显示具有强大的抗血栓形成功效，并且不会延长肾脏的出血时间。优异的疗效和安全性相结合，强有力地验证了PAR4拮抗作用是一种有前途的抗血栓形成机制。
更新日期：2019-06-27
中文翻译：
发现具有体内抗血栓功效的强蛋白酶激活的受体4拮抗剂。
为了确定新型抗血栓形成剂，我们通过在猴子血栓形成模型中开发和评估工具化合物UDM-001651，研究了蛋白酶激活的受体4（PAR4）拮抗作用。从高通量筛选开始，我们确定了基于咪唑并噻二唑的PAR4拮抗剂化学型。详细的结构-活性关系研究能够优化有效，选择性和口服生物利用的PAR4拮抗剂UDM-001651。UDM-001651在猴子血栓形成模型中进行了评估，显示具有强大的抗血栓形成功效，并且不会延长肾脏的出血时间。优异的疗效和安全性相结合，强有力地验证了PAR4拮抗作用是一种有前途的抗血栓形成机制。
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