Abstract
Here we report on the discovery of a series of maleimides which have high potency and good selectivity for GSK-3beta. The incorporation of polar groups afforded compounds with good bioavailability. The most potent compound 34 has an IC(50) of 0.6nM for GSK-3beta, over 100-fold selectivity against a panel of other kinases, and shows efficacy in rat osteoporosis models. The X-ray structure of GSK-3beta protein with 34 bound revealed the binding mode of the template and provided insights for future optimization opportunities.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Crystallography, X-Ray
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Disease Models, Animal
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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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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacokinetics
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Maleimides / chemical synthesis
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Maleimides / chemistry*
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Maleimides / pharmacokinetics
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Mice
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Protein Kinase C / metabolism
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Rats
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Structure-Activity Relationship
Substances
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Indoles
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Maleimides
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Protein Kinase Inhibitors
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Gsk3b protein, rat
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Protein Kinase C
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Glycogen Synthase Kinase 3