Discovery of Pyridazinopyridinones as Potent and Selective p38 Mitogen-Activated Protein Kinase Inhibitors

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• 作者：Bin Wu ; Hui-Ling Wang ; Liping Pettus ; Ryan P. Wurz ; Elizabeth M. Doherty ; Bradley Henkle ; Helen J. McBride ; Christiaan J. M. Saris ; Lu Min Wong ; Matthew H. Plant ; Lisa Sherman ; Matthew R. Lee ; Faye Hs
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 9, 2010
• 年：2010
• 卷：53
• 期：17
• 页码：6398-6411
• 全文大小：1196K
• 年卷期：v.53,no.17(September 9, 2010)
• ISSN：1520-4804

文摘

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.