Abstract
4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cytokines / antagonists & inhibitors*
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Cytokines / biosynthesis*
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Disease Models, Animal
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Kinetics
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Lipopolysaccharides / pharmacology
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Models, Molecular
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Molecular Conformation
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Osteoarthritis / prevention & control
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Pyrazolones / chemical synthesis*
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Pyrazolones / chemistry
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Pyrazolones / pharmacology*
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Rats
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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Cytokines
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Enzyme Inhibitors
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Lipopolysaccharides
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Pyrazolones
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Tumor Necrosis Factor-alpha
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p38 Mitogen-Activated Protein Kinases