Abstract
The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity.
Copyright © 2012 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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Cytochrome P-450 Enzyme System / metabolism
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Drug Design*
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Drug Evaluation, Preclinical
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Humans
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Imidazoles / chemistry
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Imidazoles / metabolism
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Lipopolysaccharides / toxicity
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Liver / drug effects
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Liver / metabolism
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Mice
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase 14 / metabolism
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Naphthalenes / chemistry
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Naphthalenes / 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 / toxicity
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Protein Structure, Tertiary
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Pyrazoles / chemistry
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Pyrazoles / metabolism
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Pyridines / chemistry
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Pyridines / metabolism
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Pyrimidines / chemistry*
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Tumor Necrosis Factor-alpha / blood
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Urea / analogs & derivatives*
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Urea / chemical synthesis
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Urea / toxicity
Substances
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Imidazoles
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Lipopolysaccharides
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Naphthalenes
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Protein Kinase Inhibitors
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Pyrazoles
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Pyridines
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Pyrimidines
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Tumor Necrosis Factor-alpha
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pyrazole
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Urea
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Cytochrome P-450 Enzyme System
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Mitogen-Activated Protein Kinase 14
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doramapimod
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pyrimidine
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SB 203580