Himbacine-derived thrombin receptor antagonists: c7-spirocyclic analogues of vorapaxar.

ABSTRACT: We have synthesized several C7-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound 5c from this series showed excellent PAR-1 activity (K i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure-activity relationships in this series.

SUBMITTER: Chelliah MV 

PROVIDER: S-EPMC4027741 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature