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

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posted on 2016-02-05, 15:58 authored by 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
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.

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