3-Amino-7-phthalazinylbenzoisoxazoles as a Novel Class of Potent, Selective, and Orally Available Inhibitors of p38α Mitogen-Activated Protein Kinase

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• 作者：Liping H. Pettus ; Shimin Xu ; Guo-Qiang Cao ; Partha P. Chakrabarti ; Robert M. Rzasa ; Kelvin Sham ; Ryan P. Wurz ; Dawei Zhang ; Scott Middleton ; Bradley Henkle ; Matthew H. Plant ; Christiaan J. M. Saris ; L
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 23, 2008
• 年：2008
• 卷：51
• 期：20
• 页码：6280-6292
• 全文大小：301K
• 年卷期：v.51,no.20(October 23, 2008)
• ISSN：1520-4804

文摘

The p38 mitogen-activated protein kinase (MAPK) 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, osteoporosis, and many other diseases where aberrant cytokine signaling is the driver of disease. Herein, we describe a novel class of 3-amino-7-phthalazinylbenzoisoxazole-based inhibitors. With relatively low molecular weight, these compounds are highly potent in enzyme and cell-based assays, with minimal protein shift in 50% human whole blood. Compound 3c was efficacious (ED₅₀ = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model.