作为凝血因子Xa抑制剂的异恶唑啉衍生物的设计与合成。2.

Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.

作者信息

Quan M L, Ellis C D, Liauw A Y, Alexander R S, Knabb R M, Lam G, Wright M R, Wong P C, Wexler R R

机构信息

DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.

出版信息

J Med Chem. 1999 Jul 29;42(15):2760-73. doi: 10.1021/jm980406a.

DOI:10.1021/jm980406a

PMID:10425087

Abstract

Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.

摘要

血管内血栓形成是多种心血管疾病的重要因素。因此，预防血液凝固已成为新型治疗药物的主要靶点。一种有吸引力的方法是抑制凝血因子Xa（FXa），该酶直接负责凝血酶的激活。在此，我们报道了一系列异恶唑啉衍生物，它们是有效的FXa抑制剂。对异恶唑啉环季碳位置的侧链进行优化得到了SK549，其对FXa的抑制活性达到亚纳摩尔水平（K(i)为0.52 nM）。与凝血酶和胰蛋白酶相比，SK549对FXa具有良好的选择性，在兔动静脉血栓形成模型中具有强大的抗血栓作用，并且相对于该系列中评估的其他化合物，其药代动力学有所改善。