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 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.
Peat
Andrew J
AJ
GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA. ajp25551@gsk.com
Garrido
Dulce
D
Boucheron
Joyce A
JA
Schweiker
Stephanie L
SL
Dickerson
Scott H
SH
Wilson
Jayme R
JR
Wang
Tony Y
TY
Thomson
Stephen A
SA
D000818:Animals; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular
D004791:Enzyme Inhibitors; D006835:Hydrazones; D038362:Glycogen Synthase Kinase 3