Chelliah Mariappan V, Chackalamannil Samuel, Xia Yan, Greenlee William J, Ahn Ho-Sam, Kurowski Stan, Boykow George, Hsieh Yunsheng, Chintala Madhu
Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033-1300, United States.
ACS Med Chem Lett. 2013 Dec 18;5(2):183-7. doi: 10.1021/ml400452v. eCollection 2014 Feb 13.
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.
我们合成了几种vorapaxar的C7-氨甲基类似物，它们是有效的PAR-1拮抗剂。这些类似物中的许多在大鼠中显示出优异的体外结合亲和力和药代动力学特征。该系列中的化合物6a显示出优异的PAR-1活性（K i = 5 nM）。我们还合成了一种vorapaxar的C9a-羟基类似物，它显示出非常好的PAR-1亲和力（K i = 19.5 nM），同时在食蟹猴中具有优异的大鼠药代动力学特征和体内外疗效。
