Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc

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• 作者：Benjamin P. Fauber ; Gladys de Leon Boenig ; Brenda Burton ; C茅line Eidenschenk ; Christine Everett ; Alberto Gobbi ; Sarah G. Hymowitz ; Adam R. Johnson ; Marya Liimatta ; Peter Lockey ; Maxine Norman ; Wenjun Ouyang ; Olivier Ren茅 ; Harvey Wong
• 关键词：RORc ; ROR纬 ; T0901317 ; X-ray structure ; IL-17 ; Inflammation ; Autoimmune
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 December, 2013
• 年：2013
• 卷：23
• 期：24
• 页码：6604-6609
• 全文大小：1456 K

文摘

The structure-activity relationships of T0901317 analogs were explored as RORc inverse agonists using the principles of property- and structure-based drug design. An X-ray co-crystal structure of T0901317 and RORc was obtained and provided molecular insight into why T0901317 functioned as an inverse agonist of RORc; whereas, the same ligand functioned as an agonist of FXR, LXR, and PXR. The structural data was also used to design inhibitors with improved RORc biochemical and cellular activities. The improved inhibitors possessed enhanced selectivity profiles (rationalized using the X-ray crystallographic data) against other nuclear receptors.