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. 2005 Sep 22;48(19):5884-7.
doi: 10.1021/jm0502236.

Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents

Samuel Chackalamannil  1 , Yan Xia, William J Greenlee, Martin Clasby, Darìo Doller, Hsingan Tsai, Theodros Asberom, Michael Czarniecki, Ho-Sam Ahn, George Boykow, Carolyn Foster, Jacqueline Agans-Fantuzzi, Matthew Bryant, Janice Lau, Madhu Chintala
Affiliations

Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents

Samuel Chackalamannil et al. J Med Chem. .

Abstract

Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.

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