Xie Zhouling, Meng Zhiwei, Yang Xiaoxiao, Duan Yajun, Wang Qin, Liao Chenzhong
Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P. R. China.
Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, P. R. China.
J Med Chem. 2023 Apr 27;66(8):5332-5363. doi: 10.1021/acs.jmedchem.2c02130. Epub 2023 Apr 10.
Factor XIa (FXIa) in the intrinsic pathway of the coagulation process has been proven to be an effective and safe target for anticoagulant discovery with limited or no bleeding. Numerous small-molecule FXIa inhibitors (SMFIs) with various scaffolds have been identified in the early stages of drug discovery. They have served as the foundation for the recent discovery of additional promising SMFIs with improved potency, selectivity, and pharmacokinetic profiles, some of which have entered clinical trials for the treatment of thrombosis. After reviewing the coagulation process and structure of FXIa, this perspective discusses the rational or structure-based design, discovery, structure-activity relationships, and development of SMFIs disclosed in recent years. Strategies for identifying more selective and druggable SMFIs are provided, paving the way for the design and discovery of more useful SMFIs for anticoagulation therapy.
凝血过程内源性途径中的因子XIa（FXIa）已被证明是发现抗凝剂的有效且安全的靶点，出血风险有限或无出血风险。在药物发现的早期阶段，已鉴定出许多具有各种骨架的小分子FXIa抑制剂（SMFI）。它们为最近发现其他具有更高效力、选择性和药代动力学特征的有前景的SMFI奠定了基础，其中一些已进入治疗血栓形成的临床试验。在回顾了FXIa的凝血过程和结构后，本观点讨论了近年来公开的SMFI的合理或基于结构的设计、发现、构效关系及开发。还提供了识别更具选择性和可成药的SMFI的策略，为设计和发现更有效的抗凝血治疗SMFI铺平了道路。
