title: 2-Benzenesulfonyl-8a-benzyl-hexahydro-2H-isoquinolin-6-ones as selective glucocorticoid receptor antagonists.
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.
authors.affiliation: Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA. rclark@corcept.com
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Ray
authors.forename: Paul
authors.initials: P
authors.lastname: Blaney
authors.forename: Peter H
authors.initials: PH
authors.lastname: Crackett
authors.forename: Christopher
authors.initials: C
authors.lastname: Hurley
authors.forename: Karen
authors.initials: K
authors.lastname: Williams
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Dyke
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lockey
authors.forename: Rene
authors.initials: R
authors.lastname: Devos
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Anne
authors.initials: A
authors.lastname: White
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Belanoff
mesh_terms: 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*