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

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

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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