Han Q, Dominguez C, Stouten P F, Park J M, Duffy D E, Galemmo R A, Rossi K A, Alexander R S, Smallwood A M, Wong P C, Wright M M, Luettgen J M, Knabb R M, Wexler R R
DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
J Med Chem. 2000 Nov 16;43(23):4398-415. doi: 10.1021/jm000113t.
Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.
血栓性疾病是导致死亡和发病的主要原因。在凝血级联反应中，凝血因子Xa（fXa）在正常体内平衡调节及异常血管内血栓形成过程中发挥着至关重要的作用。基于分子模拟研究，设计并合成了一系列新型的fXa抑制剂，这些抑制剂在P1位含有一个脒基6,5-稠合双环部分。构效关系（SAR）研究已产生了选择性的亚纳摩尔级fXa抑制剂。该系列中最有效的fXa抑制剂（72，SE170）具有强大的抑制常数（K(i)=0.3 nM），对fXa的选择性是对胰蛋白酶的350倍，并且在兔动静脉血栓形成模型中也显示出良好的体内疗效（ID(50)=0.14 μmol/kg/h）。完成了72与牛胰蛋白酶复合物的X射线晶体结构，并基于与人去-Gla-fXa的建模提出了72与fXa的结合模式。
