title: 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 5c from this series showed excellent PAR-1 activity (K 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.
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: Keith
authors.initials: K
authors.lastname: Eagen
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
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: Hsingan
authors.initials: H
authors.lastname: Tsai
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: PAR-1 antagonist; himbacine; thrombin receptor; vorapaxar