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

  • J Med Chem. 2010 Dec 9;53(23):8241-51. doi: 10.1021/jm100957a.
Bingwei V Yang  1 ,  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
Affiliations
  • 1. Bristol-Myers Squibb Company, Research and Development, Princeton, New Jersey 08543-4000, United States.
PMID: 21073190 DOI: 10.1021/jm100957a
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.