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.
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.
Olesen
Preben H
PH
Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. phol@novonordisk.com
Sørensen
Anders R
AR
Ursø
Birgitte
B
Kurtzhals
Peter
P
Bowler
Andrew N
AN
Ehrbar
Ulrich
U
Hansen
Bo F
BF
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006003:Glycogen / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014867:Water; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D015534:Trans-Activators; D014230:Triazoles; D051176:beta Catenin; D014867:Water; D006003:Glycogen; D038362:Glycogen Synthase Kinase 3