Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4

  • J Med Chem. 2022 Jul 14;65(13):8843-8854. doi: 10.1021/acs.jmedchem.2c00359.
E Scott Priestley  1 Jacques Banville  2 Daniel Deon  2 Laurence Dubé  2 Marc Gagnon  2 Julia Guy  2 Philippe Lapointe  2 Jean-François Lavallée  2 Alain Martel  2 Serge Plamondon  2 Roger Rémillard  2 Edward Ruediger  2 François Tremblay  2 Shana L Posy  1 Victor R Guarino  1 Jeremy M Richter  1 Jianqing Li  1 Anuradha Gupta  3 Muthalagu Vetrichelvan  3 T J Balapragalathan  3 Arvind Mathur  1 Ji Hua  1 Mario Callejo  2 Jocelyne Guay  2 Chi Shing Sum  1 Mary Ellen Cvijic  1 Carol Watson  1 Pancras Wong  1 Jing Yang  1 Michel Bouvier  2  4 David A Gordon  1 Ruth R Wexler  1 Anne Marinier  2  5
Affiliations
  • 1. Bristol-Myers Squibb Research & Early Development, 3551 Lawrenceville Road, Princeton, New Jersey08540, United States.
  • 2. Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Downtown Station, Montréal, QuébecH3C 3J7, Canada.
  • 3. Department of Discovery Synthesis, Biocon Bristol-Myers Squibb R&D Centre, Syngene International Ltd., Biocon Park, Plot No. 2 & 3, Bommasandra-Jigani Road, Bangalore560099, India.
  • 4. Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QuébecH3C 3J7, Canada.
  • 5. Department of Chemistry and Department of Pharmacology, Université de Montréal, P.O. Box 6128, Downtown Station, Montréal, QuébecH3C 3J7, Canada.
Abstract

Protease-activated Receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme Thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

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