Journal of Chinese Pharmaceutical Sciences ›› 2022, Vol. 31 ›› Issue (10): 727-737.DOI: 10.5246/jcps.2022.10.062

• Original articles •     Next Articles

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

Ling Zhang1,#, Wei Chen2,#, Ningning Yao1, Shuzeng Hou1,2, Zhiwei Meng1, Yi Kong2, Chenzhong Liao1,*(), Zhouling Xie1,*()   

  1. 1 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
    2 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
  • Received:2022-07-21 Revised:2022-08-15 Accepted:2022-08-25 Online:2022-10-31 Published:2022-10-31
  • Contact: Chenzhong Liao, Zhouling Xie
  • About author:
    # Ling Zhang and Wei Chen contributed to this work equally.


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.

Key words: Antithrombosis, Anticoagulants, Factor XIa, Bleeding risk, Structure-activity relationship