1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity.
Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.
Clark
Robin D
RD
Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA.
Ray
Nicholas C
NC
Williams
Karen
K
Blaney
Paul
P
Ward
Stuart
S
Crackett
Peter H
PH
Hurley
Christopher
C
Dyke
Hazel J
HJ
Clark
David E
DE
Lockey
Peter
P
Devos
Rene
R
Wong
Melanie
M
Porres
Soraya S
SS
Bright
Colin P
CP
Jenkins
Robert E
RE
Belanoff
Joseph
J
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001372:Aza Compounds; D007546:Isoquinolines; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid