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 IV, a series of 3-substituted 5-amidobenzoate derivatives were designed, synthesized, and identified as promising P2Y14R antagonists. The optimal compound 45 (methyl 3-(1H-benzo[d]imidazol-2-yl)-5-(2-(p-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 45 demonstrated significant anti-inflammatory efficacy, effectively mitigating the pulmonary infiltration of immune cells and inflammatory response through suppressing the NLRP3 signaling pathway. Thus, 45 with potent P2Y14R antagonistic activity, in vitro and vivo efficacy, and favorable druggability can be a strategy for treating acute lung injury and can be optimized in further studies.