Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.

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Betageri R, Gilmore T, Kuzmich D, Kirrane TM, Bentzien J, Wiedenmayer D, Bekkali Y, Regan J, Berry A, Latli B, Kukulka AJ, Fadra TN, Nelson RM, Goldrick S, Zuvela-Jelaska L, Souza D, Pelletier J, Dinallo R, Panzenbeck M, Torcellini C, Lee H, Pack E, Harcken C, Nabozny G, Thomson DS

Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.

Bioorg Med Chem Lett. 2011 Nov 15;21(22):6842-51. doi: 10.1016/j.bmcl.2011.09.018. Epub 2011 Sep 10.

PubMed ID
21963986 [ View in PubMed
]
Abstract

We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
DexamethasoneGlucocorticoid receptorIC 50 (nM)3N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)0.51N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)1.8N/AN/ADetails
DexamethasoneGlucocorticoid receptorEC 50 (nM)17N/AN/ADetails
PrednisoloneGlucocorticoid receptorIC 50 (nM)15N/AN/ADetails
PrednisoloneGlucocorticoid receptorIC 50 (nM)7N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)19N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)16N/AN/ADetails