强效和选择性双芳基马来酰亚胺糖原合成酶激酶3抑制剂的研发
The development of potent and selective bisarylmaleimide GSK3 inhibitors.
作者信息
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
机构信息
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
出版信息
Bioorg Med Chem Lett. 2005 Feb 15;15(4):899-903. doi: 10.1016/j.bmcl.2004.12.063.
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 (</=5 nM) with >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).
许多3-芳基-4-(1,2,3,4-四氢[1,4]二氮杂卓并[6,7,1-hi]吲哚-7-基)马来酰亚胺表现出强效的GSK3抑制活性(IC(50)<100 nM)，尽管很少有化合物对CDK2、CDK4或PKCβII表现出显著的选择性(>100倍)。然而，将3-(咪唑并[1,2-a]吡啶-3-基)、3-(吡唑并[1,5-a]吡啶-3-基)或氮杂类似物与马来酰亚胺上的4-(2-酰基-(1,2,3,4-四氢[1,4]二氮杂卓并[6,7,1-hi]吲哚-7-基))基团结合，得到了非常强效的GSK3抑制剂(≤5 nM)，对CDK2/4和PKCβII的选择性>160至>10000倍。这些化合物还抑制细胞中的tau蛋白磷酸化，并在2型糖尿病大鼠模型(ZDF大鼠)中有效降低血糖。
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