Design, Synthesis and Anti-Inflammatory Evaluation of 3-Substituted 5-Amidobenzoate Derivatives as Novel P2Y₁₄ Receptor Antagonists via Structure-Guided Molecular Hybridization

The P2Y₁₄R is activated by UDP and UDP glucose and is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y₁₄R antagonists and the crystallographic overlap study between PPTN and compound <b>IV</b>, a series of 3-substituted 5-amidobenzoate derivatives were designed, synthesized, and identified as promising P2Y₁₄R antagonists. The optimal compound <b>45</b> (methyl 3-(1<i>H</i>-benzo[<i>d</i>]imidazol-2-yl)-5-(2-(<i>p</i>-tolyl) acetamido)benzoate, IC₅₀ = 0.70 ± 0.01 nM) showed a strong binding ability to P2Y₁₄R, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In the LPS-induced acute lung injury model, compound <b>45</b> demonstrated significant anti-inflammatory efficacy, effectively mitigating the pulmonary infiltration of immune cells and inflammatory response through suppressing the NLRP3 signaling pathway. Thus, <b>45</b> with potent P2Y₁₄R antagonistic activity, <i>in vitro</i> and <i>vivo</i> efficacy, and favorable druggability can be a strategy for treating acute lung injury and can be optimized in further studies.