Discovery and Evaluation of 7-Alkyl-1,5-bis-aryl-pyrazolopyridinones as Highly Potent, Selective, and Orally Efficacious Inhibitors of p38α Mitogen-Activated Protein KinaseAtomic coordinates and

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• 作者：Liping H. Pettus ; Ryan P. Wurz ; Shimin Xu ; Brad Herberich ; Bradley Henkle ; Qiurong Liu ; Helen J. McBride ; Sharon Mu ; Matthew H. Plant ; Christiaan J. M. Saris ; Lisa Sherman ; Lu Min Wong ; Samer Chmait
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：April 8, 2010
• 年：2010
• 卷：53
• 期：7
• 页码：2973-2985
• 全文大小：1124K
• 年卷期：v.53,no.7(April 8, 2010)
• ISSN：1520-4804

文摘

The p38α mitogen-activated protein (MAP) kinase is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1β and tumor necrosis factor α. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, and Crohn’s disease, as well as other diseases where aberrant cytokine signaling is the driver of disease. In this communication, we describe a novel class of 7-alkyl-1,5-bis-aryl-pyrazolopyridinone-based p38α inhibitors. In particular, compound 3f is highly potent in the enzyme and cell-based assays, selective in an Ambit kinase screen, and efficacious (ED₅₀ ≤ 0.01 mg/kg) in the rat collagen induced arthritis (CIA) model.