RESUMEN
A novel class of GSK-3 inhibitors with favorable water solubility was identified in a HTS screen. SAR studies identified bioisosteric structural moieties in this class of compounds. The compounds were tested in a GSK-3 inhibition assay at 100 microM ATP giving IC(50)'s in the range from 0.1 to 10 microM. The compounds are ATP competitive inhibitors. They modulate glycogen metabolism and stimulate the accumulation of intracellular beta-catenin in whole cell assays with EC(50)'s in the range from 2 to 18 microM and 4.5-44 microM, respectively. For selected compounds, only a 10-fold lower potency was obtained in cellular assays compared to the potency obtained for inhibition of the isolated enzyme, reflecting a good cell permeability of this compound class. At 10 microM of test compound a 3-fold stimulation of the glycogen synthesis in rat soleus muscle was obtained compared to the level of glycogen synthesis observed at 0.2 nM insulin. This stimulation of glycogen synthesis is comparable to the maximal stimulation by insulin itself.