2. Academic Validation
  3. Design, synthesis and biological evaluation of novel FXIa inhibitors featuring five-membered heterocycles as P2' fragments

Design, synthesis and biological evaluation of novel FXIa inhibitors featuring five-membered heterocycles as P2' fragments

  • Eur J Med Chem. 2026 Feb 5:303:118457. doi: 10.1016/j.ejmech.2025.118457.
Jie Wu 1,  Xiaoqian Wang 2,  Huachao Zhu 3,  Ping Gong 4,  Tonghui Wang 5
Affiliations

Affiliations

  • 1 College of Pharmacy, Qilu Medical University, Zibo, Shandong, 255300, China. Electronic address: [email protected].
  • 2 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 College of Pharmacy, Qilu Medical University, Zibo, Shandong, 255300, China.
  • 4 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: [email protected].
  • 5 College of Pharmacy, Qilu Medical University, Zibo, Shandong, 255300, China. Electronic address: [email protected].
PMID: 41401594 DOI: 10.1016/j.ejmech.2025.118457
Abstract

Thrombus formation within blood vessels poses a serious threat to human health and is closely associated with various cardiovascular disorders. Therefore, developing novel anticoagulants with reduced bleeding risk holds significant clinical importance. Factor XIa (FXIa), a key enzyme in the intrinsic coagulation pathway, has emerged as an attractive target for safer anticoagulant therapy. In this study, a series of novel small-molecule FXIa inhibitors were designed based on the scaffold of Asundexian through a bioisosteric replacement strategy. Starting from compound F22, structural optimization at the P2' region was conducted by replacing the amide with non-classical heterocycles, aiming to improve inhibitory potency, selectivity, and metabolic stability. Among the synthesized analogs, compound FE12 exhibited potent FXIa inhibition (IC50 = 4.4 nM), high selectivity over PKal (SI = 60.3), and favorable metabolic stability (T1/2 = 38.6 min in HLMs). Consistent with the in vitro enzyme assay, FE12 significantly prolonged aPTT in a dose-dependent manner, comparable to Asundexian. Molecular docking indicated that FE12 retains key hydrogen-bonding and water-mediated interactions within the FXIa active site, whereas its conformation in PKal shifts and loses these interactions, explaining its potent FXIa inhibitory activity and weak PKal inhibition. In the FeCl3-induced rat thrombosis model, FE12 effectively inhibited thrombus formation comparable to Asundexian. In the mouse tail bleeding assay, FE12 did not cause a significant prolongation of bleeding time, indicating a minimal effect on hemostasis. Furthermore, acute toxicity evaluation demonstrated its good safety and tolerability. Overall, FE12 exhibits an excellent balance of potency, selectivity and safety, representing a promising lead compound for the development of small-molecule FXIa inhibitors.

Keywords

FXIa inhibitors; In vitro activity; In vivo activity; Molecular docking; Selectivity.

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