Work

Discovery of potent and selective factor XIa inhibitors incorporating triazole-based benzoic acid as novel P2’ fragments: Molecular dynamics simulations and anticoagulant activity

Year: 2024

Type: article

Abstract: 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 (IC 50 = 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 (5000-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.

Source: European Journal of Medicinal Chemistry

DOI: 10.1016/j.ejmech.2024.117067