Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.
Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, PR China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1724-1736. doi: 10.1080/14756366.2022.2086867.
Glycogen synthase kinase 3β (GSK-3β) catalyses the hyperphosphorylation of tau protein in the Alzheimer's disease (AD) pathology. A series of novel thieno[3,2-]pyrazol-3-amine derivatives were designed and synthesised and evaluated as potential GSK-3β inhibitors by structure-guided drug rational design approach. The thieno[3,2-]pyrazol-3-amine derivative was identified as a potent GSK-3β inhibitor with an IC of 3.1 nM and showed accepted kinase selectivity. In cell levels, showed no toxicity on the viability of SH-SY5Y cells at the concentration up to 50 μM and targeted GSK-3β with the increased phosphorylated GSK-3β at Ser9. Western blot analysis indicated that decreased the phosphorylated tau at Ser396 in a dose-dependent way. Moreover, effectively increased expressions of β-catenin as well as the GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth. Therefore, the thieno[3,2-]pyrazol-3-amine derivative could serve as a promising GSK-3β inhibitor for the treatment of AD.
糖原合酶激酶 3β（GSK-3β）在阿尔茨海默病（AD）病理中催化 tau 蛋白的过度磷酸化。通过基于结构的药物合理设计方法，设计并合成了一系列新型噻吩并[3,2-]吡唑-3-胺衍生物，并将其评估为潜在的 GSK-3β 抑制剂。噻吩并[3,2-]吡唑-3-胺衍生物 被鉴定为一种有效的 GSK-3β 抑制剂，IC 为 3.1 nM，并且表现出可接受的激酶选择性。在细胞水平上， 在 50 μM 浓度下对 SH-SY5Y 细胞的活力没有毒性，并且通过增加 Ser9 磷酸化的 GSK-3β 来靶向 GSK-3β。Western blot 分析表明， 以剂量依赖性方式降低 Ser396 磷酸化的 tau。此外， 还能有效增加β-连环蛋白以及 GAP43、N-myc 和 MAP-2 的表达，并促进分化神经元的神经突生长。因此，噻吩并[3,2-]吡唑-3-胺衍生物 可以作为治疗 AD 的有前途的 GSK-3β 抑制剂。
