1. The development of potent and selective bisarylmaleimide GSK3 inhibitors.
- Author
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Engler TA, Malhotra S, Burkholder TP, Henry JR, Mendel D, Porter WJ, Furness K, Diefenbacher C, Marquart A, Reel JK, Li Y, Clayton J, Cunningham B, McLean J, O'toole JC, Brozinick J, Hawkins E, Misener E, Briere D, Brier RA, Wagner JR, Campbell RM, Anderson BD, Vaughn R, Bennett DB, Meier TI, and Cook JA
- Subjects
- Animals, Blood Glucose drug effects, Cell Line, Diabetes Mellitus, Type 2 drug therapy, Disease Models, Animal, Humans, Inhibitory Concentration 50, Maleimides pharmacology, Phosphorylation drug effects, Rats, Structure-Activity Relationship, tau Proteins metabolism, Glycogen Synthase Kinase 3 antagonists & inhibitors, Maleimides chemical synthesis
- Abstract
Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
- Published
- 2005
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