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 <b>5c</b> from this series showed excellent PAR-1 activity (<i>K</i>_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