Design, synthesis and bioevaluation of 1,2,4-thiadiazolidine-3,5-dione derivatives as potential GSK-3β inhibitors for the treatment of Alzheimer's disease

Tideglusib is a non-competitive GSK-3β inhibitor which contain 1,2,4-thiadiazolidine-3,5-dione moiety, and now mainly used for progressive supranuclear palsy due to the lack of some primary cognitive endpoints and secondary endpoints in a phase IIb trail for Alzheimer's disease. Additionally, insufficient evidence exists to support that there are obvious covalent bonds between Tideglusib and GSK-3β. Targeted covalent inhibition strategy could improve the binding efficiency, selectivity and duration of kinase inhibitors. Based on the above premise, two series of targeted compounds with acryloyl warheads were designed and synthesized. The kinase inhibitory activity of the selected compound 10a with better neuroprotective effect improved 2.7 fold than that of Tideglusib. After the preliminary screening of GSK-3β inhibition and neuroprotective activity, the mechanism action of the selected compound 10a was investigated in vitro and in vivo. The results confirmed that 10a with excellent selectivity among the whole tested kinases could significantly reduce the expressions of APP and p-Tau via increasing the level of p-GSK-3β. The pharmacodynamic assay in vivo showed that 10a could markedly improve the learning and memory functions in AD mice induced by AlCl3 combined with d-galactose. At the same time, the damage of hippocampal neurons in AD mice was obviously reduced. Accordingly, the introduction of acryloyl warheads could increase the GSK-3β inhibitory activity of 1,2,4-thiadiazolidine-3,5-dione derivatives, and the selected compound 10a deserves further research as an effective GSK-3β inhibitor for the potential treatment of AD.

 

Comments：

It's interesting to see the use of targeted covalent inhibition strategy to improve the binding efficiency, selectivity, and duration of kinase inhibitors.

Compound 10a's 2.7-fold improvement in neuroprotective effect over Tideglusib, as well as its excellent selectivity among tested kinases, make it a promising candidate for further research. It's also encouraging to see that 10a can significantly reduce the expressions of APP and p-Tau while increasing the level of p-GSK-3β, which could have positive implications for treating Alzheimer's disease.

The in vivo pharmacodynamic assay showing that 10a can improve learning and memory functions and reduce damage to hippocampal neurons in AD mice is particularly noteworthy. This suggests that 10a has potential as an effective GSK-3β inhibitor for the treatment of AD.

Further research will be needed to confirm these findings and determine the safety and efficacy of compound 10a in humans. However, this study provides a promising starting point for the development of new treatments for Alzheimer's disease.

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S2823	Tideglusib	Tideglusib is an irreversible, non ATP-competitive GSK-3β inhibitor with IC50 of 60 nM in a cell-free assay; fails to inhibit kinases with a Cys homologous to Cys-199 located in the active site. Phase 2.

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