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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.

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


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.


Himbacine; PAR-1 antagonist; platelet aggregation; thrombin receptor; vorapaxar

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