Discovery of nor-seco himbacine analogs as thrombin receptor antagonists

Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey.

Graphical abstractDiscovery of a nor-seco himbacine analog derived from the tetrahydrothiopyranyl himbacine derivative and identification of an active metabolite generated in vivo are described.Figure optionsDownload full-size imageDownload as PowerPoint slide