Dimethyl-diphenyl-propanamide Derivatives As Nonsteroidal Dissociated Glucocorticoid Receptor Agonists

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-m...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-12, Vol.53 (23), p.8241-8251
Main Authors: Yang, Bingwei V, Weinstein, David S, Doweyko, Lidia M, Gong, Hua, Vaccaro, Wayne, Huynh, Tram, Xiao, Hai-yun, Doweyko, Arthur M, Mckay, Lorraine, Holloway, Deborah A, Somerville, John E, Habte, Sium, Cunningham, Mark, McMahon, Michele, Townsend, Robert, Shuster, David, Dodd, John H, Nadler, Steven G, Barrish, Joel C
Format: Article
Language:English
Subjects:
Amides - chemistry
Amides - pharmacology
Animals
Models, Molecular
Rats
Receptors, Glucocorticoid - agonists
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100957a