Design, Synthesis and Anti-Inflammatory Evaluation of 3-Substituted 5-Amidobenzoate Derivatives as Novel P2Y 14 Receptor Antagonists via Structure-Guided Molecular Hybridization

作者：S.-Y. Mao, Wenjing Liu, Xin Wang, Mingzhu Wang, Simin Wang, Yongfang Yao, Yongtao Duan, Chuanjun Song · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.4c01539 · 被引用次数：9 · 研究领域：Adenosine and Purinergic Signaling、Pharmacological Receptor Mechanisms and Effects、Neuropeptides and Animal Physiology

The P2Y 14 R is activated by UDP and UDP glucose and is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2Y 14 R 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 P2Y 14 R antagonists. The optimal compound 45 (methyl 3-(1 H -benzo[ d ]imidazol-2-yl)-5-(2-( p -tolyl) acetamido)benzoate, IC 50 = 0.70 ± 0.01 nM) showed a strong binding ability to P2Y 14 R, 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 P2Y 14 R 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.