Author/Authors :
Robin D. Clark، نويسنده , , Nicholas C. Ray، نويسنده , , Paul Blaney، نويسنده , , Peter H. Crackett، نويسنده , , Christopher Hurley، نويسنده , , Karen Williams، نويسنده , , Hazel J. Dyke، نويسنده , , David E. Clark، نويسنده , , Peter M. Lockey، نويسنده , , René Devos، نويسنده , , Melanie Wong، نويسنده , , Anne White، نويسنده , , Joseph K. Belanoff، نويسنده ,
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.
