Abstract
Novel indolylindazolylmaleimides were synthesized and examined for kinase inhibition. We identified low-nanomolar inhibitors of PKC-beta with good to excellent selectivity vs other PKC isozymes and GSK-3beta. In a cell-based functional assay, 8f and 8i effectively blocked IL-8 release induced by PKC-betaII (IC(50) = 20-25 nM). In cardiovascular safety assessment, representative lead compounds bound to the hERG channel with high affinity, potently inhibited ion current in a patch-clamp experiment, and caused a dose-dependent increase of QT(c) in guinea pigs.
MeSH terms
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Animals
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Cell Line
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / chemistry
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Glycogen Synthase Kinase 3 beta
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Guinea Pigs
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Humans
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Indazoles / chemical synthesis*
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Indazoles / pharmacology
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Indazoles / toxicity
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Indoles / chemical synthesis*
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Indoles / pharmacology
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Indoles / toxicity
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Interleukin-8 / metabolism
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Long QT Syndrome / chemically induced
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Maleimides / chemical synthesis*
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Maleimides / pharmacology
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Maleimides / toxicity
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Models, Molecular
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Patch-Clamp Techniques
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Potassium Channel Blockers / chemical synthesis
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Potassium Channel Blockers / chemistry
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Potassium Channel Blockers / pharmacology
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Potassium Channels, Voltage-Gated / drug effects
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Potassium Channels, Voltage-Gated / metabolism
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase C / chemistry
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Protein Kinase C beta
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Structure-Activity Relationship
Substances
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Indazoles
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Indoles
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Interleukin-8
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Isoenzymes
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KCNH2 protein, human
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Maleimides
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Potassium Channel Blockers
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Potassium Channels, Voltage-Gated
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Protein Kinase C
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Protein Kinase C beta
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Glycogen Synthase Kinase 3