Discovery of Potent and Selective Quinoxaline-Based Protease-Activated Receptor 4 (PAR4) Antagonists for the Prevention of Arterial Thrombosis
X. Zhang, Wen Jiang, Jeremy M. Richter, Jay Bates, Samuel K. Reznik, Sylwia Stachura, Richard Rampulla, Dyamanna Doddalingappa, Ulaganathan Sankar, Ji Hua, Jeffrey S. Bostwick, Chi Shing Sum, Shana Posy, Sarah E. Malmstrom, Joyce Dickey, David Harden, R. Michael Lawrence, Victor R. Guarino, William A. Schumacher, Pancras C. Wong, Jing Yang, David A. Gordon, Ruth R. Wexler, E. Scott Priestley
Abstract
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 μM 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 γ-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.