Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity.

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Biggadike K, Boudjelal M, Clackers M, Coe DM, Demaine DA, Hardy GW, Humphreys D, Inglis GG, Johnston MJ, Jones HT, House D, Loiseau R, Needham D, Skone PA, Uings I, Veitch G, Weingarten GG, McLay IM, Macdonald SJ

Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity.

J Med Chem. 2007 Dec 27;50(26):6519-34. Epub 2007 Nov 27.

PubMed ID
18038970 [ View in PubMed
]
Abstract

The synthesis and biological activity of tetrahydronaphthalene derivatives coupled to various heterocycles are described. These compounds are potent glucocorticoid receptor agonists with efficacy selectivity in an NFkappaB glucocorticoid receptor (GR) agonist assay (representing transrepression effects) over an MMTV GR agonist assay (representing transactivation effects). Quinolones, indoles, and C- and N-linked quinolines are some of the heterocycles that provide efficacy selectivity. For example, the isoquinoline 49D1E2 has NFkappaB agonism with pIC50 of 8.66 (89%) and reduced efficacy in MMTV agonism (6%), and the quinoline 55D1E1 has NFkappaB agonism with pIC50 of 9.30 (101%) and reduced efficacy in MMTV agonism with pEC50 of 8.02 (47%). A description of how a compound from each class is modeled in the active site of the receptor is given.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DexamethasoneGlucocorticoid receptorEC 50 (nM)5.01N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)7.94N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)>10000N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)1.17N/AN/ADetails
MifepristoneGlucocorticoid receptorIC 50 (nM)>1000N/AN/ADetails
MifepristoneGlucocorticoid receptorIC 50 (nM)5.75N/AN/ADetails
MifepristoneGlucocorticoid receptorIC 50 (nM)4.68N/AN/ADetails
PrednisoloneGlucocorticoid receptorIC 50 (nM)8.51N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)31.62N/AN/ADetails