title: Himbacine-derived thrombin receptor antagonists: c7-aminomethyl and c9a-hydroxy analogues of vorapaxar.
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.
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Mariappan V
authors.initials: MV
authors.lastname: Chelliah
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Chackalamannil
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenlee
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Ho-Sam
authors.initials: HS
authors.lastname: Ahn
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Kurowski
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: George
authors.initials: G
authors.lastname: Boykow
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Madhu
authors.initials: M
authors.lastname: Chintala
keywords: Himbacine; PAR-1 antagonist; platelet aggregation; thrombin receptor; vorapaxar