Design, synthesis and biological evaluation of Asundexian derivatives
10.11665/j.issn.1000-5048.2025100902
- VernacularTitle:Asundexian衍生物的设计、合成及活性评价
- Author:
Jie WU
1
;
Huachao ZHU
;
Xinhao WANG
;
Ping GONG
Author Information
1. 齐鲁医药学院药学院, 淄博 255213;沈阳药科大学制药工程学院, 沈阳 110016
- Publication Type:Journal Article 期刊文章
- Keywords:
FXIa inhibitors;
Asundexian;
bioisosterism;
biological activity
- From:
Journal of China Pharmaceutical University
2026;57(2):196-205
- CountryChina
- Language:Chinese
-
Abstract:
Coagulation factor XIa (FXIa) plays a crucial role in thrombus formation; therefore, the development of potent and safe FXIa inhibitors is of great significance. In this study, compound F22, previously discovered by our group, was selected as the lead compound. Based on the principles of bioisosterism and fragment-based drug design, four series comprising 14 novel Asundexian derivatives not previously reported in the literature were designed and synthesized. The structures of the target compounds were confirmed by 1H NMR and HRMS, and their inhibitory activities against FXIa were evaluated using chromogenic substrate assay. Results showed that compound FD-1 exhibited the most potent activity, with an IC50 value of 2.8 nmol/L, which was superior to that of the lead compound F22 (IC50 = 4.5 nmol/L) and the reference drug Asundexian (IC50 = 5.0 nmol/L). Furthermore, in the activated partial thromboplastin time (aPTT) assay, compound FD-1 demonstrated excellent anticoagulant activity, outperforming Asundexian, showing no significant effect on prothrombin time (PT). These findings provide valuable insights for further structural optimization and rational design of small-molecule FXIa inhibitors.
