2. Academic Validation
  3. Discovery of potent, highly selective, and orally bioavailable factor XIa inhibitors for anticoagulant therapy

Discovery of potent, highly selective, and orally bioavailable factor XIa inhibitors for anticoagulant therapy

  • Eur J Med Chem. 2025 Feb 25:289:117436. doi: 10.1016/j.ejmech.2025.117436.
Yajing Zhang 1,  Rong Huang 1,  Xueqin Hu 1,  Nan Zheng 2,  Lei Geng 1,  Zequn Yin 2,  Yajun Duan 2,  Qin Wang 3,  Chenzhong Liao 4,  Xiaoxiao Yang 5,  Zhouling Xie 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
  • 2 The First Affiliated Hospital of University of Science and Technology of China, Hefei, 230001, China.
  • 3 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 4 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address: czliao@hfut.edu.cn.
  • 5 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address: yangxiaoxiao@hfut.edu.cn.
  • 6 Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address: zhoulingxie@hfut.edu.cn.
PMID: 40010270 DOI: 10.1016/j.ejmech.2025.117436
Abstract

Factor XIa (FXIa) has emerged as a promising target for novel anticoagulant development since inhibiting it can reduce thrombosis without significant bleeding risks. Despite a few FXIa inhibitors entering clinical trials, none have been approved for the market yet. Here, we present highly selective and orally bioavailable FXIa inhibitors derived from compound 1, 4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-methoxypyridin-2(1H)-one. Structure-activity relationship studies led to the discovery of promising 1-(pyridin-2-ylmethyl)pyridin-2(1H)-one-based FXIa inhibitors 37, 39b, 43, and 46b, which exhibited enhanced FXIa potency and selectivity compared to asundexian, an FXIa inhibitor in phase III clinical trials. Their anticoagulant activity was also comparable to or greater than that of asundexian. Compound 43 significantly reduced thrombosis in both FeCl3-induced mouse and rabbit arterial thrombosis models, demonstrating superior efficacy compared to asundexian. Importantly, 43 did not increase bleeding risks and exhibited a favorable safety profile in mice, suggesting its potential as a promising FXIa inhibitor for the treatment of thrombosis.

Keywords

Anticoagulant; Antithrombotic activity; Factor XIa; Selectivity; Structure-activity relationship.

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