Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis

被引：5

作者：

Zhang, Xiaojun ^{[1
]}

Jiang, Wen ^{[1
]}

Richter, Jeremy M. ^{[1
]}

Bates, J. Alex ^{[1
]}

Reznik, Samuel K. ^{[1
]}

Stachura, Sylwia ^{[1
]}

Rampulla, Richard ^{[1
]}

Doddalingappa, Dyamanna ^{[2
]}

Ulaganathan, Sankar ^{[2
]}

Hua, Ji ^{[1
]}

Bostwick, Jeffrey S. ^{[1
]}

Sum, Chi ^{[1
]}

Posy, Shana ^{[1
]}

Malmstrom, Sarah ^{[1
]}

Dickey, Joyce ^{[1
]}

Harden, David ^{[1
]}

Lawrence, R. Michael ^{[1
]}

Guarino, Victor R. ^{[1
]}

Schumacher, William A. ^{[1
]}

Wong, Pancras ^{[1
]}

Yang, Jing ^{[1
]}

Gordon, David A. ^{[1
]}

Wexler, Ruth R. ^{[1
]}

Priestley, Scott ^{[1
]}

机构：

[1] Bristol Myers Squibb, Res & Early Dev, Princeton, NJ 08540 USA

[2] Syngene Int Ltd, Biocon Bristol Myers Squibb R&D Ctr, Dept Discovery Synth, Bangalore 560099, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 05期

关键词：

ANTIPLATELET THERAPY; CLOPIDOGREL; ASPIRIN; DERIVATIVES; VORAPAXAR; SERIES;

D O I：

10.1021/acs.jmedchem.3c01986

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low mu M potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48, possessing a 2 nM IC(50 )against PAR4 activation by gamma-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models.

引用

页码：3571 / 3589

页数：19

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