2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists.
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.
Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA. rclark@corcept.com
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.
PMID: 17822897 [PubMed - indexed for MEDLINE]