(Peer-Reviewed) Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors
Ling Zhang 章凌 ¹, Wei Chen 陈威 ², Ningning Yao 姚宁宁 ¹, Shuzeng Hou 侯书增 ¹, Zhiwei Meng 孟志伟 ¹, Yi Kong 孔毅 ², Chenzhong Liao 廖晨钟 ¹, Zhouling Xie 谢周令 ¹
¹ Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
中国 合肥 合肥工业大学 食品与生物工程学院 药物科学与工程系
² School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
中国 南京 中国药科大学生命科学与技术学院

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.
Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors_1
Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors_2
Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors_3
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