Abstract
A test library with three novel p38alpha inhibitory scaffolds and a narrow set of substituents was prepared. Appropriate combination of substituent and scaffold generated potent p38alpha inhibitors, for example, pyrazolo[3,4-b]pyridine 9, pyrazolo[3,4-d]pyrimidine 18a and pyrazolo[3,4-b]pyrazine 23b with potent in vivo activity upon oral administration in animal models of rheumatoid arthritis.
MeSH terms
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Administration, Oral
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Animals
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Arthritis, Experimental / drug therapy*
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Disease Models, Animal
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Mice
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
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Molecular Structure
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Pyrazines / administration & dosage*
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Pyrazines / chemical synthesis
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Pyrazines / chemistry
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Pyrazoles / administration & dosage*
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry
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Pyridines / administration & dosage*
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyrimidines / administration & dosage*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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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 / metabolism
Substances
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Enzyme Inhibitors
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Lipopolysaccharides
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Pyrazines
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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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pyrazolo(3,4-b)pyrazine
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pyrazolo(3,4-b)pyridine
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pyrazolo(3,4-d)pyrimidine
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Mitogen-Activated Protein Kinase 14