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

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

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.
PMID: 35729784 DOI: 10.1021/acs.jmedchem.2c00359
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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