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.