College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China.
School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
Eur J Med Chem. 2024 Dec 5;279:116890. doi: 10.1016/j.ejmech.2024.116890. Epub 2024 Sep 23.
The P2Y receptor (P2YR), as a crucial member of the purine family, is a potential therapeutic target for the treatment of intestinal inflammation, tracheal inflammation and diabetes. We first discovered the hit compound (5a, IC = 168.5 nM against P2YR) through our in-house library screening. Then, further medicinal chemistry efforts were made to optimize compound 5a, and a potent P2YR antagonist (5 ab) with better antagonistic activity (IC = 19.6 nM) was obtained. The molecular docking, CETSA, SPR and pull-down results indicated that compound 5 ab displayed strong binding to P2YR. Also, compound 5 ab possessed high selectivity and satisfying oral bioactivity and pharmacokinetic profiles. In experiments with LPS-induced acute lung injury in mice, after treatment with compound 5 ab, the level of inflammatory factors IL-6, TNF-α and IL-β were considerably decreased, the infiltration of immune cells was decreased. Further exploration revealed that 5 ab inhibited the expression and release of chemokines in lung tissue, suppressing the activation of the NLRP3 inflammasome. Compound 5 ab had certain anti-inflammatory abilities in vivo and in vitro. These results demonstrate that compound 5 ab is a potential P2YR antagonist and is worthy of further study.
P2Y 受体（P2YR）作为嘌呤家族的重要成员，是治疗肠道炎症、气管炎症和糖尿病的潜在治疗靶点。我们首先通过内部文库筛选发现了命中化合物（5a，对 P2YR 的 IC = 168.5 nM）。然后，我们进一步进行了药物化学研究，优化了化合物 5a，得到了一种具有更好拮抗活性（IC = 19.6 nM）的强效 P2YR 拮抗剂（5ab）。分子对接、CETSA、SPR 和下拉实验结果表明，化合物 5ab 与 P2YR 具有很强的结合能力。此外，化合物 5ab 具有高选择性和令人满意的口服生物活性和药代动力学特征。在 LPS 诱导的小鼠急性肺损伤实验中，用化合物 5ab 处理后，炎症因子 IL-6、TNF-α 和 IL-β 的水平明显降低，免疫细胞的浸润减少。进一步研究表明，5ab 抑制了肺组织中趋化因子的表达和释放，抑制了 NLRP3 炎性小体的激活。化合物 5ab 在体内和体外均具有一定的抗炎能力。这些结果表明，化合物 5ab 是一种有潜力的 P2YR 拮抗剂，值得进一步研究。
