Himbacine-Derived Thrombin Receptor Antagonists: C7‑Aminomethyl and C9a-Hydroxy Analogues of Vorapaxar

Himbacine-Derived Thrombin Receptor Antagonists: C7‑Aminomethyl and C9a-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 6a from this series showed excellent PAR-1 activity (K i = 5 nM). We have also synthe...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:ACS medicinal chemistry letters 2014-02, Vol.5 (2), p.183-187
Hauptverfasser: Chelliah, Mariappan V, Chackalamannil, Samuel, Xia, Yan, Greenlee, William J, Ahn, Ho-Sam, Kurowski, Stan, Boykow, George, Hsieh, Yunsheng, Chintala, Madhu
Format: Artikel
Sprache:eng
Schlagworte:
Letter
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml400452v