Abstract
The biphenyl amides (BPAs) are a series of p38alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.
MeSH terms
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Amides / blood
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology*
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Amino Acids / genetics
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Amino Acids / metabolism
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Binding Sites
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Biphenyl Compounds / blood
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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Drug Design
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Lipopolysaccharides / pharmacology
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Molecular Conformation
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Molecular Structure
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Naphthalenes / pharmacology
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Pyrazoles / pharmacology
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Structure-Activity Relationship
Substances
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Amides
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Amino Acids
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Biphenyl Compounds
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Lipopolysaccharides
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Naphthalenes
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Pyrazoles
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Mitogen-Activated Protein Kinase 14
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doramapimod