取代的3-咪唑并[1,2-a]吡啶-3-基-4-(1,2,3,4-四氢-[1,4]二氮杂卓并[6,7,1-hi]吲哚-7-基)吡咯-2,5-二酮作为糖原合酶激酶-3的高选择性强效抑制剂。
Substituted 3-imidazo[1,2-a]pyridin-3-yl- 4-(1,2,3,4-tetrahydro-[1,4]diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3.
作者信息
Engler Thomas A, Henry James R, Malhotra Sushant, Cunningham Brian, Furness Kelly, Brozinick Joseph, Burkholder Timothy P, Clay Michael P, Clayton Joshua, Diefenbacher Clive, Hawkins Eric, Iversen Philip W, Li Yihong, Lindstrom Terry D, Marquart Angela L, McLean Johnathan, Mendel David, Misener Elizabeth, Briere Daniel, O'Toole John C, Porter Warren J, Queener Steven, Reel Jon K, Owens Rebecca A, Brier Richard A, Eessalu Thomas E, Wagner Jill R, Campbell Robert M, Vaughn Renee
机构信息
Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
出版信息
J Med Chem. 2004 Jul 29;47(16):3934-7. doi: 10.1021/jm049768a.
Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
糖原合酶激酶-3（GSK3）参与胰岛素受体信号传导。GSK3抑制剂有望像胰岛素一样降低血糖，这使得GSK3成为治疗2型糖尿病的一个有吸引力的靶点。在此我们报告一系列强效且选择性的GSK3抑制剂的发现。化合物7 - 12在II型糖尿病体内模型中显示出口服活性，并且9和12具有理想的药代动力学性质。
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