title: 1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as selective glucocorticoid receptor antagonists with high functional activity.
abstract: 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.
authors.affiliation: Corcept Therapeutics, 149 Commonwealth Avenue, Menlo Park, CA 94025, USA.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Clark
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Ray
authors.forename: Karen
authors.initials: K
authors.lastname: Williams
authors.forename: Paul
authors.initials: P
authors.lastname: Blaney
authors.forename: Stuart
authors.initials: S
authors.lastname: Ward
authors.forename: Peter H
authors.initials: PH
authors.lastname: Crackett
authors.forename: Christopher
authors.initials: C
authors.lastname: Hurley
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Dyke
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.forename: Peter
authors.initials: P
authors.lastname: Lockey
authors.forename: Rene
authors.initials: R
authors.lastname: Devos
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Soraya S
authors.initials: SS
authors.lastname: Porres
authors.forename: Colin P
authors.initials: CP
authors.lastname: Bright
authors.forename: Robert E
authors.initials: RE
authors.lastname: Jenkins
authors.forename: Joseph
authors.initials: J
authors.lastname: Belanoff
mesh_terms: 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
chemical_list: D001372:Aza Compounds; D007546:Isoquinolines; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid