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

  • J Med Chem. 2024 Feb 22. doi: 10.1021/acs.jmedchem.3c01986.
Xiaojun Zhang  1 ,  Wen Jiang  1 ,  Jeremy M Richter  1 ,  J Alex Bates  1 ,  Samuel K Reznik  1 ,  Sylwia Stachura  1 ,  Richard Rampulla  1 ,  Dyamanna Doddalingappa  2 ,  Sankar Ulaganathan  2 ,  Ji Hua  1 ,  Jeffrey S Bostwick  1 ,  Chi Sum  1 ,  Shana Posy  1 ,  Sarah Malmstrom  1 ,  Joyce Dickey  1 ,  David Harden  1 ,  R Michael Lawrence  1 ,  Victor R Guarino  1 ,  William A Schumacher  1 ,  Pancras Wong  1 ,  Jing Yang  1 ,  David A Gordon  1 ,  Ruth R Wexler  1 ,  E Scott Priestley  1
Affiliations
  • 1. Research & Early Development, Bristol Myers Squibb, 3551 Lawrenceville Road, Princeton, New Jersey 08540, United States.
  • 2. Department of Discovery Synthesis, Biocon Bristol Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore 560099, India.
PMID: 38385264 DOI: 10.1021/acs.jmedchem.3c01986
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 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.

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