Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors  

以天冬氨酸为母核的高活性高选择性FXIa抑制剂的发现

作　　者：Ling Zhang Wei Chen Ningning Yao Shuzeng Hou Zhiwei Meng Yi Kong Chenzhong Liao Zhouling Xie 章凌;陈威;姚宁宁;侯书增;孟志伟;孔毅;廖晨钟;谢周令(合肥工业大学食品与生物工程学院药物科学与工程系,安徽合肥230009;中国药科大学生命科学与技术学院,江苏南京210009)

机构地区：[1]Department of Pharmaceutical Sciences and Engineering,School of Food and Biological Engineering,Hefei University of Technology,Hefei230009,China [2]School of Life Science and Technology,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2022年第10期727-737,共11页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No.81803352)。

摘　　要：As a coagulation factor in the intrinsic coagulation pathway,factor XIa(FXIa)is an effective and safe target for the development of antithrombotic drugs.Many small-molecule FXIa inhibitors have been discovered,some of which are being evaluated in clinical trials.However,none of them have been approved.In the present study,a highly selective potent FXIa inhibitor with poor solubility reported in our previous work was selected as a lead compound to be further modified to improve FXIa potency and physicochemical properties.The structure-based drug design and structure-activity relationship study led to the discovery of LY8,LY17,and LY25,which demonstrated enhanced FXIa potency and maintained excellent selectivity.In addition,LY8 exhibited significantly improved aqueous solubility,suggesting that it could be a promising compound to be further evaluated.作为内源性凝血途径中的凝血因子,FXIa因子是开发抗血栓药物有效和安全的靶点。迄今为止,已经有多类小分子FXIa抑制剂被报道,其中几个正处于临床试验中,但没有药物获批。本文选择了我们课题组报道的一个高活性高选择性但水溶性较差的FXIa抑制剂作为先导化合物,以进一步提高对FXIa的活性、选择性和物理化学性质。基于结构的药物设计以及构效关系研究发现了LY8、LY17和LY25三个化合物,它们在保持了很好的选择性的同时,提高了对FXIa的抑制作用。同时,LY8还表现出显著改善的水溶性,为进一步开发安全有效的抗凝血药物奠定了基础。

关 键 词：ANTITHROMBOSIS ANTICOAGULANTS Factor XIa Bleeding risk Structure-activity relationship 

分 类 号：R916[医药卫生—药学]