Synthesis and biological evaluation of thieno[3,2-]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3β inhibitors for Alzheimer's disease.

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.