3-amino-7-phthalazinylbenzoisoxazoles as a novel class of potent, selective, and orally available inhibitors of p38alpha mitogen-activated protein kinase |
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Authors: | Pettus Liping H Xu Shimin Cao Guo-Qiang Chakrabarti Partha P Rzasa Robert M Sham Kelvin Wurz Ryan P Zhang Dawei Middleton Scott Henkle Bradley Plant Matthew H Saris Christiaan J M Sherman Lisa Wong Lu Min Powers David A Tudor Yanyan Yu Violeta Lee Matthew R Syed Rashid Hsieh Faye Tasker Andrew S |
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Institution: | Department of Chemistry Research and Discovery, Amgen Inc., Thousand Oaks, California 91320, USA. lpettus@amgen.com |
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Abstract: | 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-1beta and tumor necrosis factor alpha. 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 (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model. |
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