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

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 a...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-07, Vol.47 (16), p.3934-3937
Main Authors: 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
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological and medical sciences
Diabetes Mellitus, Type 2 - drug therapy
Female
General and cellular metabolism. Vitamins
Glycogen Synthase Kinase 3 - antagonists & inhibitors
Glycogen Synthase Kinase 3 beta
Humans
Imidazoles - chemical synthesis
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Medical sciences
Pharmacology. Drug treatments
Pyridines - chemical synthesis
Pyridines - pharmacokinetics
Pyridines - pharmacology
Pyrroles - chemical synthesis
Pyrroles - pharmacokinetics
Pyrroles - pharmacology
Rats
Rats, Zucker
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049768a