Discovery of Potent Orally Active Thrombin Receptor (Protease Activated Receptor 1) Antagonists as Novel Antithrombotic Agents
Journal of Medicinal Chemistry2005Vol. 48(19), pp. 5884–5887
Citations Over TimeTop 10% of 2005 papers
Samuel Chackalamannil, Yan Xia, William J. Greenlee, Martin C. Clasby, Darı́o Doller, Hsingan Tsai, Theodros Asberom, Michael Czarniecki, Ho-Sam Ahn, George Boykow, Carolyn Foster, Jacqueline Agans-Fantuzzi, Matthew Bryant, Janice Lau, Madhu Chintala
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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