Abstract
A library of trisubstituted oxazoles, thiazoles, imidazoles (1,2,4- and 2,4,5-substituted) and imidazo[1,2-b]pyridines was prepared and evaluated in vitro as p38alpha inhibitors and in vivo in several models of rheumatoid arthritis. Four structures--32, 37, 45 and 59--were identified as potent inhibitors of p38alpha with high efficacy in the LPS induced TNFalpha release model in the mouse, the adjuvant induced arthritis and the collagen induced arthritis in the rat with ED50s between 1.0 and 9.5 mg/kg p.o.
MeSH terms
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Animals
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Antirheumatic Agents / chemical synthesis*
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Antirheumatic Agents / pharmacology
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Antirheumatic Agents / therapeutic use
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy
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Collagen
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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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Imidazoles / chemistry
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Lipopolysaccharides / pharmacology
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Mice
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Oxazoles / chemistry
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Pyridines / chemical synthesis*
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Pyridines / pharmacology
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Pyridines / therapeutic use
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Rats
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Structure-Activity Relationship
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Thiazoles / chemistry
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Substances
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Antirheumatic Agents
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Enzyme Inhibitors
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Imidazoles
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Lipopolysaccharides
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Oxazoles
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Pyridines
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Thiazoles
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Tumor Necrosis Factor-alpha
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Collagen
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p38 Mitogen-Activated Protein Kinases