Design, Synthesis and Anti-Inflammatory Evaluation of 3-Substituted 5-Amidobenzoate Derivatives as Novel P2Y Receptor Antagonists via Structure-Guided Molecular Hybridization.

The P2YR is activated by UDP and UDP glucose and is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2YR antagonists and the crystallographic overlap study between PPTN and compound , a series of 3-substituted 5-amidobenzoate derivatives were designed, synthesized, and identified as promising P2YR antagonists. The optimal compound (methyl 3-(1-benzo[]imidazol-2-yl)-5-(2-(-tolyl) acetamido)benzoate, IC = 0.70 ± 0.01 nM) showed a strong binding ability to P2YR, high selectivity, moderate oral bioactivity, and improved pharmacokinetic profiles. In the LPS-induced acute lung injury model, compound demonstrated significant anti-inflammatory efficacy, effectively mitigating the pulmonary infiltration of immune cells and inflammatory response through suppressing the NLRP3 signaling pathway. Thus, with potent P2YR antagonistic activity, and efficacy, and favorable druggability can be a strategy for treating acute lung injury and can be optimized in further studies.