Identification of dissociated non-steroidal glucocorticoid receptor agonists

A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. A new series of ligands for the glucocorticoid recep...

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Published in:Bioorganic & medicinal chemistry letters 2007-09, Vol.17 (18), p.5025-5031
Main Authors: Kuzmich, Daniel, Kirrane, Tom, Proudfoot, John, Bekkali, Younes, Zindell, Renee, Beck, Laura, Nelson, Richard, Shih, Cheng-Kon, Kukulka, Alison J., Paw, Zofia, Reilly, Patty, Deleon, Rodney, Cardozo, Mario, Nabozny, Gerald, Thomson, David
Format: Article
Language:English
Subjects:
Anti-inflammatory
Aromatase
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Glucocorticoid receptor
Glucocorticoid receptor agonist
Glucocorticoids - agonists
IL-6
Ligands
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.07.031