Research and Development, Bristol-Myers Squibb , P.O. Box 5400, Princeton, New Jersey 08543, United States.
J Med Chem. 2014 Dec 11;57(23):9915-32. doi: 10.1021/jm5010607. Epub 2014 Dec 2.
Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
新型 FXIa 抑制剂含有（S）-2-苯基-1-（4-苯基-1H-咪唑-2-基）乙胺核心，经过优化得到化合物 16b，它是一种有效的、可逆的 FXIa 抑制剂（Ki = 0.3 nM），在兔动静脉分流血栓模型中具有体内抗血栓作用（ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)）。最初的类似物选择是通过使用化合物 11a 和 11h 进行分子建模，并将其叠加到四氢喹啉 3 与 FXIa 复合物的 X 射线晶体结构上得到的。进一步的优化是通过仔细分析 FXIa/11h 复合物的 X 射线晶体结构得出的特定修饰来实现的。化合物 16b 耐受性良好，能够对 FXIa 机制进行广泛的药理学评估，直至血栓抑制的 ID90。
