Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.

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Clackers M, Coe DM, Demaine DA, Hardy GW, Humphreys D, Inglis GG, Johnston MJ, Jones HT, House D, Loiseau R, Minick DJ, Skone PA, Uings I, McLay IM, Macdonald SJ

Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics.

Bioorg Med Chem Lett. 2007 Sep 1;17(17):4737-45. Epub 2007 Jun 26.

PubMed ID
17616395 [ View in PubMed
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Abstract

Starting from an established series of non-steroidal glucocorticoid receptor (GR) agonists, a large array was designed where a metabolically labile benzoxazinone moiety was replaced. Initial hits bound to GR but lacked agonist activity. Following two further iterations, potent GR agonists were discovered with 20D1E1 having NFkappaB agonism pIC(50) 8.8 (103%). Other analogues such as 23D1E1 display a dissociated profile (NFkappaB pIC(50) 8.1 (103%), MMTV pEC(50) 7.02 (36%)). The tetrahydronaphthalene moiety can also be replaced with substituted aryls such as 24E1 and 25E1.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DexamethasoneGlucocorticoid receptorIC 50 (nM)7.6N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)1N/AN/ADetails
MifepristoneGlucocorticoid receptorIC 50 (nM)6.9N/AN/ADetails
MifepristoneGlucocorticoid receptorIC 50 (nM)11N/AN/ADetails