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

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

Journal of medicinal chemistry (2005-09-16)
Samuel Chackalamannil, 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
PMID16161991
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.