2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists.

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Clark RD, Ray NC, Blaney P, Crackett PH, Hurley C, Williams K, Dyke HJ, Clark DE, Lockey PM, Devos R, Wong M, White A, Belanoff JK

2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists.

Bioorg Med Chem Lett. 2007 Oct 15;17(20):5704-8. Epub 2007 Aug 19.

PubMed ID
17822897 [ View in PubMed
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Abstract

The 2-azadecalin ring system was evaluated as a scaffold for the preparation of glucocorticoid receptor (GR) antagonists. High affinity, selective GR antagonists were discovered based on a hypothetical binding mode related to the steroidal GR antagonist RU-43044. 2-Benzenesulfonyl substituted 8a-benzyl-hexahydro-2H-isoquinolin-6-ones exemplified by (R)-37 had low nanomolar affinity for GR with moderate functional activity (200 nM) in a reporter gene assay. These compounds were devoid of affinity for other steroidal receptors (ER, AR, MR, and PR). Analogues based on an alternative putative binding mode (CP-like) were found to be inactive.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MifepristoneGlucocorticoid receptorKi (nM)0.82N/AN/ADetails
MifepristoneGlucocorticoid receptorKi (nM)1.2N/AN/ADetails
MifepristoneGlucocorticoid receptorKi (nM)0.4N/AN/ADetails