Abstract
The p38 mitogen-activated protein kinase (MAPK) plays an important role in the production of proinflammatory cytokines, making it an attractive target for the treatment of various inflammatory diseases. A series of pyridazinopyridinone compounds were designed as novel p38 kinase inhibitors. A structure-activity investigation identified several compounds possessing excellent potency in both enzyme and human whole blood assays. Among them, compound 31 exhibited good pharmacokinetic properties and showed excellent selectivity against other related kinases. In addition, 31 demonstrated efficacy in a collagen-induced arthritis disease model in rats.
MeSH terms
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Activating Transcription Factor 2 / metabolism
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Animals
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Antirheumatic Agents / chemical synthesis*
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Antirheumatic Agents / pharmacokinetics
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Antirheumatic Agents / pharmacology
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Arthritis, Experimental / chemically induced
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Arthritis, Experimental / drug therapy
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Binding Sites
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Collagen
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Female
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Humans
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Interleukin-8 / biosynthesis
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Interleukin-8 / blood
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Lipopolysaccharides / pharmacology
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Male
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Models, Molecular
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Phosphorylation
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacokinetics
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Pyridazines / pharmacology
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Pyridones / chemical synthesis*
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Rats
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Rats, Inbred Lew
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / pharmacology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Substances
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Activating Transcription Factor 2
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Antirheumatic Agents
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Interleukin-8
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Lipopolysaccharides
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N-cyclopropyl-3-(8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido(3,2-d)pyridazin-3-yl)-4-methylbenzamide
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Pyridazines
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Pyridones
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Tumor Necrosis Factor-alpha
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Collagen
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p38 Mitogen-Activated Protein Kinases