2. Academic Validation
  3. Discovery of Potent Protease-Activated Receptor 4 Antagonists with in Vivo Antithrombotic Efficacy

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

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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