Lessons learnt from glycogen synthase kinase 3 inhibitors development for Alzheimer's disease

Glycogen synthase kinase 3 (GSK-3) inhibitors have aroused a great interest for medicinal chemists and pharmaceutical companies in the last years. In fact, some candidates have reached to clinical trials as disease modifying drugs for Alzheimer's disease. This review will cover the great improvements recently done in the field of GSK-3 inhibitors switching from random discovery to rational drug design, from full GSK-3 inhibition to mild and controlled activity of enzyme reduction, from unknown therapeutic potential to validated efficacy in different animal models of diseases. Moreover some lessons learnt from clinical trials will be described with the aim to improve future designs. Collective results highlight the importance of mild GSK-3 inhibitors as innovative drugs for severe human unmet diseases.