Synthesis and in Vitro Characterization of 1-(4-Aminofurazan-3-yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic Acid Derivatives. A New Class of Selective GSK-3 Inhibitors

• Published in: Journal of medicinal chemistry 2003-07, Vol.46 (15), p.3333-3341
• Main Authors: Olesen, Preben H, Sørensen, Anders R, Ursø, Birgitte, Kurtzhals, Peter, Bowler, Andrew N, Ehrbar, Ulrich, Hansen, Bo F
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin; Biological and medical sciences; CHO Cells; Cricetinae; Cytoskeletal Proteins - metabolism; Databases, Factual; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Glycogen - biosynthesis; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Humans; In Vitro Techniques; Male; Medical sciences; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Solubility; Structure-Activity Relationship; Trans-Activators - metabolism; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Water
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm021095d

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 μM ATP giving IC50's in the range from 0.1 to 10 μM. The compounds are ATP competitive inhibitors. They modulate glycogen metabolism and stimulate the accumulation of intracellular β-catenin in whole cell assays with EC50's in the range from 2 to 18 μM and 4.5−44 μM, 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 μM 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.