Identification of a novel pyrrolo[2,3-]pyridine compound as a potent glycogen synthase kinase 3β inhibitor for treating Alzheimer's disease.

Herein, a novel pyrrolo[2,3-]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, , was rationally designed and synthesised to target Alzheimer's disease (AD). inhibited GSK-3β, with an IC of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, showed low cytotoxicity to SH-SY5Y cells, significantly upregulated the expression of β-catenin and neurogenesis-related biomarkers, and effectively promoted the outgrowth of differentiated neuronal neurites. Moreover, substantially ameliorated dyskinesia in AlCl-induced zebrafish AD models at a concentration of 0.12 μM, which was more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed the safety of in vivo. Our findings suggested that is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.