Journal of medicinal chemistry · 2010
Discovery of pyridazinopyridinones as potent and selective p38 mitogen-activated protein kinase inhibitors.
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Wu Bin, Wang Hui-Ling, Pettus Liping, Wurz Ryan P, Doherty Elizabeth M, Henkle Bradley, McBride Helen J, Saris Christiaan J M, Wong Lu Min, Plant Matthew H, Sherman Lisa, Lee Matthew R, Hsieh Faye, Tasker Andrew S
Аннотация
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.
Предметные рубрики MeSH
Activating Transcription Factor 2AnimalsAntirheumatic AgentsArthritis, ExperimentalBinding SitesCollagenFemaleHumansInterleukin-8LipopolysaccharidesMaleModels, MolecularPhosphorylationPyridazinesPyridonesRatsRats, Inbred LewRats, Sprague-DawleyStructure-Activity RelationshipTumor Necrosis Factor-alphap38 Mitogen-Activated Protein Kinases