Yao Ningning, Jia Zhiping, Tian Yongbin, Hou Shuzeng, Yang Xiaoxiao, Han Jihong, Duan Yajun, Liao Chenzhong, Kong Yi, Xie Zhouling
Department of Pharmaceutical Sciences and Engineering, School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, P.R. China.
School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, P.R. China.
J Med Chem. 2022 Mar 10;65(5):4318-4334. doi: 10.1021/acs.jmedchem.1c02153. Epub 2022 Feb 27.
FXIa inhibition has been a promising strategy for treating thrombotic diseases. Up to date, many small-molecule FXIa inhibitors have been identified; however, most of them exhibit undesirable selectivity over the homologous plasma kallikrein (PKal). By employing structure-based drug design strategies, we identified many novel selective FXIa inhibitors that have extra interactions with the S2 subsite of FXIa. Among them, compound displayed good inhibitory activity against FXIa and high selectivity over PKal and even several other serine proteases. Additionally, showed significant anticoagulant activity toward the intrinsic pathway without affecting the extrinsic pathway. In vivo, exhibited significant antithrombotic activity without increasing the bleeding risk and obvious toxicity in mice, demonstrating that it could be a promising candidate for further research. This study first demonstrates the importance of the S2 subsite of FXIa, paving the way to design highly selective FXIa inhibitors for clinical uses.
抑制因子XIa（FXIa）一直是治疗血栓性疾病的一种有前景的策略。迄今为止，已鉴定出许多小分子FXIa抑制剂；然而，它们中的大多数对同源血浆激肽释放酶（PKal）表现出不理想的选择性。通过采用基于结构的药物设计策略，我们鉴定出许多新型的选择性FXIa抑制剂，它们与FXIa的S2亚位点有额外的相互作用。其中，化合物对FXIa表现出良好的抑制活性，对PKal甚至其他几种丝氨酸蛋白酶具有高选择性。此外，对内在途径显示出显著的抗凝活性，而不影响外在途径。在体内，在小鼠中表现出显著的抗血栓活性，而不增加出血风险和明显毒性，表明它可能是进一步研究的有前景的候选药物。本研究首次证明了FXIa的S2亚位点的重要性，为设计用于临床的高选择性FXIa抑制剂铺平了道路。
