Mao Shuqiang, Liu Wenjin, Wang Xin, Wang Mingzhu, Wang Simin, Yao Yongfang, Duan Yongtao, Song Chuanjun
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
J Med Chem. 2025 Feb 13;68(3):2483-2503. doi: 10.1021/acs.jmedchem.4c01539. Epub 2025 Jan 29.
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.
P2YR 可被 UDP 和 UDP 葡萄糖激活，并参与多种人类炎症性疾病。基于目前报道的 P2YR 拮抗剂的分子对接分析以及 PPTN 与化合物之间的晶体学重叠研究，设计、合成了一系列 3-取代 5-氨基苯甲酸酯衍生物，并将其鉴定为有前景的 P2YR 拮抗剂。最佳化合物（3-(1-苯并[1,3]咪唑-2-基)-5-(2-(对甲苯基)乙酰胺基)苯甲酸甲酯，IC = 0.70 ± 0.01 nM）对 P2YR 表现出强结合能力、高选择性、适度的口服生物活性以及改善的药代动力学特征。在脂多糖诱导的急性肺损伤模型中，化合物表现出显著的抗炎功效，通过抑制 NLRP3 信号通路有效减轻免疫细胞的肺浸润和炎症反应。因此，具有强效 P2YR 拮抗活性、抗炎功效且具备良好成药性的该化合物可作为治疗急性肺损伤的一种策略，并可在进一步研究中进行优化。
