Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists

Bingwei V. Yang, David S. Weinstein, Lidia M. Doweyko, Hua Gong, Wayne Vaccaro, Tram Huynh, Hai Yun Xiao, Arthur M. Doweyko, Lorraine McKay, Deborah A. Holloway, John E. Somerville, Sium Habte, Mark Cunningham, Michele McMahon, Robert Townsend, David Shuster, John H. Dodd, Steven G. Nadler, Joel C. Barrish

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Abstract

A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.

Original languageEnglish (US)
Pages (from-to)8241-8251
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number23
DOIs
Publication statusPublished - Dec 9 2010

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Yang, B. V., Weinstein, D. S., Doweyko, L. M., Gong, H., Vaccaro, W., Huynh, T., ... Barrish, J. C. (2010). Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists. Journal of Medicinal Chemistry, 53(23), 8241-8251. https://doi.org/10.1021/jm100957a