Clasby Martin C, Chackalamannil Samuel, Czarniecki Michael, Doller Dario, Eagen Keith, Greenlee William, Kao Grace, Lin Yan, Tsai Hsingan, Xia Yan, Ahn Ho-Sam, Agans-Fantuzzi Jacqueline, Boykow George, Chintala Madhu, Foster Carolyn, Smith-Torhan April, Alton Kevin, Bryant Matthew, Hsieh Yunsheng, Lau Janice, Palamanda Jairam
Central Nervous System and Cardiovascular Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
J Med Chem. 2007 Jan 11;50(1):129-38. doi: 10.1021/jm061043e.
The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.
我们对原型凝血酶受体拮抗剂1（Ki = 2.7 nM）的代谢进行了研究，发现了三种主要代谢物（2、4和5）。通过合成独立验证了代谢物的结构。化合物4被证明是一种有效的凝血酶受体拮抗剂，Ki = 11 nM。此外，在食蟹猴口服给药后的激动剂诱导的体外血小板聚集试验中，化合物4相对于1的效力提高了3倍；给药后24小时观察到60%的抑制率，该活性得以维持。化合物4在功能试验中具有高活性，在大鼠和猴子中显示出优异的口服生物利用度。与化合物1相比，化合物4显示出更好的大鼠酶诱导谱，使其能够替代化合物1作为开发候选物。
