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The development of potent and selective bisarylmaleimide GSK3 inhibitors |
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| Authors: | Engler Thomas A Malhotra Sushant Burkholder Timothy P Henry James R Mendel David Porter Warren J Furness Kelly Diefenbacher Clive Marquart Angela Reel Jon K Li Yihong Clayton Joshua Cunningham Brian McLean Johnathan O'toole John C Brozinick Joseph Hawkins Eric Misener Elizabeth Briere Daniel Brier Richard A Wagner Jill R Campbell Robert M Anderson Bryan D Vaughn Renee Bennett Donald B Meier Timothy I Cook James A |
| Affiliation: | Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. engler_thomas@lilly.com |
| 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). |
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