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

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Yang BV, Weinstein DS, Doweyko LM, Gong H, Vaccaro W, Huynh T, Xiao HY, Doweyko AM, McKay L, Holloway DA, Somerville JE, Habte S, Cunningham M, McMahon M, Townsend R, Shuster D, Dodd JH, Nadler SG, Barrish JC

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

J Med Chem. 2010 Dec 9;53(23):8241-51. doi: 10.1021/jm100957a. Epub 2010 Nov 12.

PubMed ID
21073190 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DexamethasoneGlucocorticoid receptorKi (nM)1.1N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)2.5N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)1.1N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)4.2N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)5N/AN/ADetails
PrednisoloneGlucocorticoid receptorKi (nM)1.5N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)15.8N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)13.6N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)82.7N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)57.4N/AN/ADetails