Himbacine-Derived Thrombin Receptor Antagonists: C<sub>7</sub>‑Aminomethyl and C<sub>9a</sub>-Hydroxy Analogues of
Vorapaxar
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Abstract
We have synthesized several C<sub>7</sub>-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 <b>6a</b> from this series showed excellent
PAR-1 activity (<i>K</i><sub>i</sub> = 5 nM). We have also
synthesized a C<sub>9a</sub>-hydroxy analogue of vorapaxar, which
showed very good PAR-1 affinity (<i>K</i><sub>i</sub> =
19.5 nM) along with excellent rat pharmacokinetic profile and ex vivo
efficacy in the cynomolgus monkey
