Xun Qing-Qing, Zhang Jing, Li Yan-Peng, Li Ying, Ma Yu-Ying, Chen Zhao-Bin, Ding Le-Ping, Shi Xiao-Long
Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China; School of Clinical Medicine, Jining Medical University, Jining, Shandong, China.
Medical Research Center, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, China.
Eur J Med Chem. 2025 Mar 5;285:117236. doi: 10.1016/j.ejmech.2025.117236. Epub 2025 Jan 2.
The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer's disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70 % at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl-induced zebrafish AD models and exhibited its low-toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.
强效糖原合酶激酶-3β（GSK-3β）抑制剂的研发日益被视为针对阿尔茨海默病（AD）多因素致病机制的候选治疗方法。本研究基于结构导向的合理设计制备了各种新型吡咯并[2,3-b]吡啶衍生物，评估了其抗AD活性并检测了安全性。我们的结果表明，许多吡咯并[2,3-b]吡啶衍生物具有较强的GSK-3β抑制活性，特别是化合物41、46和54，其半数抑制浓度（IC）分别为0.22、0.26和0.24 nM，并且它们各自对24种结构相似的激酶通常具有GSK-3β选择性。此外，在细胞水平上的进一步靶向研究表明，化合物41剂量依赖性地增加了Ser9位点的GSK-3β磷酸化，以抑制GSK-3β活性，从而通过降低p-tau-Ser396丰度来抑制tau蛋白的过度磷酸化。此外，41上调了β-连环蛋白和神经发生相关标志物（GAP43和MAP-2），从而促进了SH-SY5Y细胞中神经元的神经突生长。根据体外细胞试验，41对SH-SY5Y细胞的细胞毒性较低，在100 μM浓度下存活率超过70%。体内药效和急性毒性实验表明，41有效改善了氯化铝诱导的斑马鱼AD模型中的运动障碍，并在C57BL/6小鼠中表现出低毒性。总体而言，吡咯并[2,3-b]吡啶衍生物41可作为一种有前景的治疗AD的GSK-3β抑制剂。
