Abstract
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Copyright © 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Dogs
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Female
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Hepatocytes / metabolism
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High-Throughput Screening Assays
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / metabolism
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Macaca mulatta
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Male
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Mice
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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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Quinolines / chemical synthesis
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Quinolines / chemistry*
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Quinolines / pharmacokinetics
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Rats
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Semicarbazides / chemical synthesis
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Semicarbazides / chemistry*
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Semicarbazides / pharmacokinetics
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Structure-Activity Relationship
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Thiourea / analogs & derivatives*
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Thiourea / chemical synthesis
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Thiourea / chemistry
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Thiourea / pharmacokinetics
Substances
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Protein Kinase Inhibitors
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Quinolines
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Semicarbazides
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thiosemicarbazide
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quinoline
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I-kappa B Kinase
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Thiourea