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
血栓性疾病是死亡和发病的主要原因。Xa因子(fXa)在凝血级联反应中的正常稳态和异常血管内血栓形成的调节中起着至关重要的作用。基于分子模型研究,已经设计并合成了一系列新的fXa
抑制剂,这些
抑制剂在P1位置掺入了酰胺基6,5-稠合的双环部分。结构活性关系(
SAR)研究已导致选择性的纳摩尔fXa
抑制剂。该系列中最有效的fXa
抑制剂(72,
SE170)具有有效的抑制常数(K(i)= 0.3 nM),对fXa的选择性是胰
蛋白酶的350倍,并且在兔动脉硬化中也显示出良好的体内功效静脉血栓形成模型(ID(50)= 0.14 micromol / kg / h)。完成了与牛胰
蛋白酶复合的X射线晶体结构72