ACS Med Chem Lett. 2013 Dec 18;5(2):183-7. doi: 10.1021/ml400452v. eCollection 2014 Feb 13.

Himbacine-derived thrombin receptor antagonists: c7-aminomethyl and c9a-hydroxy analogues of vorapaxar.

Chelliah MV¹, Chackalamannil S¹, Xia Y¹, Greenlee WJ¹, Ahn HS¹, Kurowski S¹, Boykow G¹, Hsieh Y¹, Chintala M¹.

Author information

1: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.

Abstract

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 6a from this series showed excellent PAR-1 activity (K i = 5 nM). We have also synthesized a C9a-hydroxy analogue of vorapaxar, which showed very good PAR-1 affinity (K i = 19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo efficacy in the cynomolgus monkey.