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
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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.
Journal of Medicinal Chemistry 10/2005; 48(19):5884-7. · 5.25 Impact Factor
