Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy

  • J Med Chem. 2019 Aug 22;62(16):7400-7416. doi: 10.1021/acs.jmedchem.9b00186.
Michael M Miller  1 ,  Jacques Banville  2 ,  Todd J Friends  1 ,  Mark Gagnon  2 ,  Jon J Hangeland  1 ,  Jean-François Lavallée  2 ,  Alain Martel  2 ,  Harold O'Grady  1 ,  Roger Rémillard  2 ,  Edward Ruediger  2 ,  François Tremblay  2 ,  Shana L Posy  3 ,  Nick J Allegretto  1 ,  Victor R Guarino  1 ,  David G Harden  4 ,  Timothy W Harper  1 ,  Karen Hartl  1 ,  Jonathan Josephs  1 ,  Sarah Malmstrom  1 ,  Carol Watson  1 ,  Yanou Yang  1 ,  Ge Zhang  1 ,  Pancras Wong  1 ,  Jing Yang  1 ,  Michel Bouvier  2  5 ,  Dietmar A Seiffert  1 ,  Ruth R Wexler  1 ,  R Michael Lawrence  1 ,  E Scott Priestley  1 ,  Anne Marinier  2
Affiliations
  • 1. Bristol-Myers Squibb Research & Development , 311 Pennington-Rocky Hill Road , Pennington , New Jersey 08534 , United States.
  • 2. Institute for Research in Immunology and Cancer , Université de Montréal , P.O. Box 6128, Downtown Station , Montréal , Québec H3C 3J7 , Canada.
  • 3. Bristol-Myers Squibb Research & Development , 3551 Lawrenceville Road , Princeton , New Jersey 08540 , United States.
  • 4. Bristol-Myers Squibb Research & Development , 5 Research Parkway , Wallingford , Connecticut 06492 , United States.
  • 5. Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Québec H3C 3J7 , Canada.
PMID: 31246024 DOI: 10.1021/acs.jmedchem.9b00186
Abstract

In an effort to identify novel antithrombotics, we have investigated Protease-activated Receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 Antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 Antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

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