Novel GSK-3 inhibitors with improved cellular activity

A novel series of [1-(1H-benzimidazol-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl] arylhydrazones was synthesized and shown to potently inhibit glycogen synthase kinase-3 (GSK-3). In light of detailed structure-activity relationships and structural knowledge of the GSK-3 binding pocket, a benzimidazole s...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2004-05, Vol.14 (9), p.2127-2130
Main Authors: PEAT, Andrew J, GARRIDO, Dulce, BOUCHERON, Joyce A, SCHWEIKER, Stephanie L, DICKERSON, Scott H, WILSON, Jayme R, WANG, Tony Y, THOMSON, Stephen A
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line
Dogs
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
General and cellular metabolism. Vitamins
Glycogen Synthase Kinase 3 - antagonists & inhibitors
Hydrazones - chemistry
Hydrazones - pharmacology
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
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Summary:A novel series of [1-(1H-benzimidazol-7-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl] arylhydrazones was synthesized and shown to potently inhibit glycogen synthase kinase-3 (GSK-3). In light of detailed structure-activity relationships and structural knowledge of the GSK-3 binding pocket, a benzimidazole substituent was incorporated onto the pyrazolopyrimidine core resulting in improved potency over previous analogs. More importantly, these derivatives show low nanomolar efficacy for stimulating glycogen synthesis in vitro and therefore may be useful in the treatment of type 2 diabetes mellitus.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2004.02.037