Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Aminomethyl and C_9a-Hydroxy Analogues of Vorapaxar

We have synthesized several C₇-aminomethyl analogues of vorapaxar that are potent PAR-1 antagonists. Many of these analogues showed excellent in vitro binding affinity and pharmacokinetics profile in rats. Compound <b>6a</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5 nM). We have also synthesized a C_9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (<i>K</i>_i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey

Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Spirocyclic Analogues of Vorapaxar

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