Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang 24, Nanjing, 210009, China.
Eur J Med Chem. 2019 Nov 1;181:111564. doi: 10.1016/j.ejmech.2019.111564. Epub 2019 Jul 26.
The P2Y receptor (P2YR) plays a key role in the modulation of inflammatory process, but very few classes of antagonists have been reported. A series of 3-amide benzoic acid derivatives were identified as novel and potent P2YR antagonists. The most potent antagonist, 16c, showed comparable activity (IC = 1.77 nM) to PPTN, the most potent P2YR antagonist reported. Compound 16c demonstrated dramatically improved aqueous solubility and excellent metabolic stability in rat and human microsomes. Investigation of the anti-inflammatory effect of 16c was performed in MSU treated THP-1 cells by flow cytometry, Western Blot and immunofluorescence labeling technology, which exhibited that 16c might be a promising candidate for further research.
P2Y 受体（P2YR）在炎症过程的调节中起着关键作用，但报道的拮抗剂种类非常少。一系列 3-酰胺苯甲酸衍生物被鉴定为新型有效的 P2YR 拮抗剂。最有效的拮抗剂 16c 的活性与报道的最强 P2YR 拮抗剂 PPTN 相当（IC50=1.77nM）。化合物 16c 在大鼠和人微粒体中表现出显著改善的水溶解度和优异的代谢稳定性。通过流式细胞术、Western Blot 和免疫荧光标记技术，在 MSU 处理的 THP-1 细胞中研究了 16c 的抗炎作用，结果表明 16c 可能是进一步研究的有前途的候选药物。
