Abstract
The identification and progression of a potent and selective series of isoquinoline inhibitors of IkappaB kinase-beta (IKK-beta) are described. Hit-generation chemistry based on IKK-beta active-site knowledge yielded a weakly potent but tractable chemotype that was rapidly progressed into a series with robust enzyme and cellular activity and significant selectivity over IKK-alpha.
MeSH terms
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Drug Discovery*
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / chemistry
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I-kappa B Kinase / metabolism
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Inhibitory Concentration 50
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Isoquinolines / chemistry*
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Isoquinolines / metabolism
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Isoquinolines / pharmacology*
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Models, Molecular
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Molecular Conformation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
Substances
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Isoquinolines
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Protein Kinase Inhibitors
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I-kappa B Kinase