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

doi:10.5246/jcps.2022.10.062

Abstract

Abstract:

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

Supporting:

Ling Zhang, Wei Chen, Ningning Yao, Shuzeng Hou, Zhiwei Meng, Yi Kong, Chenzhong Liao, Zhouling Xie. Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(10): 727-737.

Figures/Tables 9

Table 1. Inhibitory activity against FXIa of LY1–LY5.

Table 2. Inhibitory activity against FXIa of LY6–LY30.

Table 3. Selectivity profiles and aqueous solubility of LY8, LY17, and LY25.

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