Abstract
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.
MeSH terms
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Administration, Oral
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Animals
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Brain / drug effects
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Brain / metabolism*
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Discovery*
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Molecular
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Molecular Structure
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Niacinamide / administration & dosage
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Niacinamide / chemistry
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Niacinamide / pharmacokinetics*
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Niacinamide / pharmacology*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Protein Kinase Inhibitors
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Niacinamide
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isonicotinamide
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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glycogen synthase kinase 3 alpha