Design, synthesis and biological evaluation of Asundexian derivatives

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. Their structures were confirmed by ¹H NMR and MS. The inhibitory activities of the target compounds against FXIa were evaluated using a chromogenic substrate assay. Among them, 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 aPTT assay, FD-1 demonstrated excellent anticoagulant activity (EC_2x = 0.5 µmol/L), outperforming Asundexian (EC_2x = 0.6 µmol/L), while showing no significant effect on PT. These findings provide valuable insights for the further structural optimization and rational design of small-molecule FXIa inhibitors.