Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.
The first stereoselective synthesis of the hexahydroimidazo[1,5b]isoquinoline (HHII) scaffold as a surrogate for the steroidal A-B ring system is described. The structure-activity relationships of the analogs derived from this scaffold show that the basic imidazole moiety is tolerated by the glucocorticoid receptor (GR) in terms of binding affinity, although the partial agonist activity in the transrepressive assays depends on the substitution pattern on the B-ring. More importantly, most compounds in the HHII series bearing a tertiary alcohol moiety on the B-ring are either inactive or significantly less active in inducing GR-mediated transactivation, thus displaying a "dissociated" pharmacology in vitro.
Xiao
Hai-Yun
HY
Bristol-Myers Squibb Company, Research and Development, Princeton, New Jersey 08543-4000, USA.
Wu
Dauh-Rurng
DR
Malley
Mary F
MF
Gougoutas
Jack Z
JZ
Habte
Sium F
SF
Cunningham
Mark D
MD
Somerville
John E
JE
Dodd
John H
JH
Barrish
Joel C
JC
Nadler
Steven G
SG
Dhar
T G Murali
TG
D003907:Dexamethasone / Q000494:pharmacology; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects; D015394:Molecular Structure; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D019040:E-Selectin; D007546:Isoquinolines; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone