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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.
Bioorganic & medicinal chemistry letters, 02/2005, Letnik: 15, Številka: 4Journal Article
3-(Imidazo1,2- apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5- apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1- hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1- hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC 50), although few show significant selectivity (>100 ×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2- apyridin-3-yl), 3-(pyrazolo1,5- apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1- hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. 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).
