Factor XIa (FXIa) has emerged as a novel anticoagulant target with a reduced risk of bleeding. However, due to the nearly identical residues it shares with its closest homologue, plasma kallikrein (PKa), only a few selective FXIa inhibitors have been reported. Herein, we describe the discovery of novel triazole-based pyridone derivatives as potent and selective FXIa inhibitors. Structural optimization identified triazole-based benzoic acids as optimal P2’ fragments. The representative compound (S)-10h (IC₅₀ = 0.38 nM for FXIa) was approximately 3-fold more potent than asundexian for FXIa, along with up to 150-fold selectivity over PKa (13-fold for asundexian) and up to 100,000-fold selectivity over FXa and thrombin (5,000-fold for asundexian). Extensive molecular dynamics simulations and free energy calculations revealed that electrostatic interactions with varied residues near the binding site, particularly the loop at the bottom of the S2’ pocket (IP-loop), are critical factors contributing to the improved selectivity over PKa. Calculations of electrostatic potential (ESP) surfaces illustrated that FXIa forms a more positive ESP than PKa, thrombin, and FXa, which attracts the carboxylic acid group of the designed compounds, enhancing both potency and selectivity. Moreover, compound (S)-10h demonstrated potent in vitro anticoagulant activity with an EC_1.5X value of 0.55 μM for aPTT, without interfering with PT up to 100 μM. Thus, compound (S)-10h represents a promising lead for further optimization as a novel anticoagulant agent.

中文翻译：

---

发现以三唑为基础的苯甲酸作为新型 P2' 片段的强效和选择性因子 XIa 抑制剂：分子动力学模拟和抗凝活性


因子 XIa （FXIa） 已成为一种新的抗凝剂靶点，可降低出血风险。然而，由于它与最接近的同源物血浆激肽释放酶 （PKa） 共享几乎相同的残基，因此仅报道了少数选择性 FXIa 抑制剂。在本文中，我们描述了新型基于三唑的吡啶酮衍生物作为有效和选择性 FXIa 抑制剂的发现。结构优化确定三唑基苯甲酸为最佳 P2' 片段。代表性化合物 （S）-10h （FXIa 的 IC₅₀ = 0.38 nM） 比 ASUNDEXIAN 的 FXIa 强约 3 倍，选择性比 PKa 高 150 倍（ASUNDEXIAN 的 13 倍），比 FXa 和凝血酶的选择性高 100,000 倍（ASUNDEXIAN 的 5,000 倍）。广泛的分子动力学模拟和自由能计算表明，与结合位点附近各种残基的静电相互作用，特别是 S2' 口袋底部的环（IP-环）是导致 PKa 选择性提高的关键因素。静电电位 （ESP） 表面的计算表明，FXIa 形成比 PKa、凝血酶和 FXa 更正的 ESP，后者吸引设计化合物的羧酸基团，从而提高效力和选择性。此外，化合物 （S）-10h 显示出有效的体外抗凝活性，对 aPTT 的 EC_值为 0.55 μM，而不会干扰高达 100 μM 的 PT。因此，化合物 （S）-10h 代表了作为新型抗凝剂进一步优化的有前途的线索。