Version 2 2024-02-23, 23:03Version 2 2024-02-23, 23:03
Version 1 2024-02-22, 10:29Version 1 2024-02-22, 10:29
journal contribution
posted on 2024-02-23, 23:03authored byXiaojun Zhang, Wen Jiang, Jeremy M. Richter, J. Alex Bates, Samuel K. Reznik, Sylwia Stachura, Richard Rampulla, Dyamanna Doddalingappa, Sankar Ulaganathan, Ji Hua, Jeffrey S. Bostwick, Chi Sum, Shana Posy, Sarah Malmstrom, Joyce Dickey, David Harden, R. Michael Lawrence, Victor R. Guarino, William A. Schumacher, Pancras Wong, Jing Yang, David A. Gordon, Ruth R. Wexler, E. Scott Priestley
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
IC50 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.