GSK-3 inhibitor 4 is an orally active and brain-permeable compound that acts as a triple inhibitor of GSK-3, CDK2, and CDK5, with IC50 values of 0.56 nM (GSK-3β), 0.45 nM (GSK-3α), 0.47 μM (CDK2), and 0.68 μM (CDK5). It effectively reduces Tau protein levels and can be used in the study of Alzheimer's disease.

GSK-3β:0.56 nM, CDK2:0.47 μM, CDK5:0.68 μM, GSK-3α:0.45 nM

GSK-3 inhibitor 4 (compound 40) demonstrates excellent selectivity and efficacy against CDK2 (840-fold, IC50 = 0.47 μM), CDK5 (1200-fold, IC50 = 0.68 μM), GSK-3β (IC50 = 0.56 nM), and GSK-3α (IC50 = 0.45 nM). It also exhibits good permeability and a high capacity for binding to plasma proteins and brain tissue due to its lipophilicity.[1]

GSK-3 inhibitor 4 (10 mg/kg; p.o.) reduced pTau396 by 37% when administered orally as a nanosuspension. GSK-3 inhibitor 4 (2 mg/kg, i.v.; 10 mg/kg, p.o.) exhibits low to moderate clearance (15.8 to 23.3 mL/min/kg) and is well absorbed orally in solution.[1]