Discovery of Isonicotinamides as Highly Selective, Brain Penetrable, and Orally Active Glycogen Synthase Kinase-3 Inhibitors

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• 作者：Guanglin Luo ; Ling Chen ; Catherine R. Burton ; Hong Xiao ; Prasanna Sivaprakasam ; Carol M. Krause ; Yang Cao ; Nengyin Liu ; Jonathan Lippy ; Wendy J. Clarke ; Kimberly Snow ; Joseph Raybon ; Vinod Arora ; Matt Pokross ; Kevin Kish ; Hal A. Lewis ; David R. Langley ; John E. Macor ; Gene M. Dubowchik
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：59
• 期：3
• 页码：1041-1051
• 全文大小：512K
• ISSN：1520-4804

文摘

GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation of diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition of GSK-3 may be useful in treating a number of diseases including Alzheimer’s disease (AD), type II diabetes, mood disorders, and some cancers, but the approach poses significant challenges. Here, we present a class of isonicotinamides that are potent, highly kinase-selective GSK-3 inhibitors, the members of which demonstrated oral activity in a triple-transgenic mouse model of AD. The remarkably high kinase selectivity and straightforward synthesis of these compounds bode well for their further exploration as tool compounds and therapeutics.