| Abstract
| - The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and threemajor metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independentlyby synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activitywas sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functionalassays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior ratenzyme induction profile relative to compound 1, allowing it to replace compound 1 as a developmentcandidate.
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