2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists.
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.
Clark
Robin D
RD
Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA. rclark@corcept.com
Ray
Nicholas C
NC
Blaney
Paul
P
Crackett
Peter H
PH
Hurley
Christopher
C
Williams
Karen
K
Dyke
Hazel J
HJ
Clark
David E
DE
Lockey
Peter M
PM
Devos
Rene
R
Wong
Melanie
M
White
Anne
A
Belanoff
Joseph K
JK
D001554:Benzene / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry*