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

Glycogen synthase kinase 3 beta (GSK-3 beta) catalyses the hyperphosphorylation of tau protein in the Alzheimer's disease (AD) pathology. A series of novel thieno[3,2-c]pyrazol-3-amine derivatives were designed and synthesised and evaluated as potential GSK-3 beta inhibitors by structure-guided drug rational design approach. The thieno[3,2-c]pyrazol-3-amine derivative 16b was identified as a potent GSK-3 beta inhibitor with an IC50 of 3.1 nM in vitro and showed accepted kinase selectivity. In cell levels, 16b showed no toxicity on the viability of SH-SY5Y cells at the concentration up to 50 mu M and targeted GSK-3 beta with the increased phosphorylated GSK-3 beta at Ser9. Western blot analysis indicated that 16b decreased the phosphorylated tau at Ser396 in a dose-dependent way. Moreover, 16b effectively increased expressions of beta-catenin as well as the GAP43, N-myc, and MAP-2, and promoted the differentiated neuronal neurite outgrowth. Therefore, the thieno[3,2-c]pyrazol-3-amine derivative 16b could serve as a promising GSK-3 beta inhibitor for the treatment of AD.

Automated summary

A series of novel thieno[3,2-c]pyrazol-3-amine derivatives were designed and synthesized as potential GSK-3 beta inhibitors, among which 16b was identified as a potent inhibitor. At the cellular level, 16b showed no toxicity and effectively promoted neuronal differentiation and neurite outgrowth.