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Novel synthesis of the hexahydroimidazo[1,5b]isoquinoline scaffold: application to the synthesis of glucocorticoid receptor modulators.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Feb 11; Vol. 53 (3), pp. 1270-80. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Dexamethasone pharmacology
E-Selectin genetics
E-Selectin metabolism
Genes, Reporter
HeLa Cells
Humans
Isoquinolines chemistry
Lung cytology
Lung drug effects
Molecular Structure
Promoter Regions, Genetic
Structure-Activity Relationship
Transcription, Genetic
Transcriptional Activation
Isoquinolines chemical synthesis
Isoquinolines pharmacology
Receptors, Glucocorticoid agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20047280
- Full Text :
- https://doi.org/10.1021/jm901551w