Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or “dissociated” agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 indu...

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Published inJournal of medicinal chemistry Vol. 52; no. 6; pp. 1731 - 1743
Main Authors Robinson, Ralph P, Buckbinder, Leonard, Haugeto, Amber I, McNiff, Patricia A, Millham, Michele L, Reese, Matthew R, Schaefer, Jean F, Abramov, Yuriy A, Bordner, Jon, Chantigny, Yves A, Kleinman, Edward F, Laird, Ellen R, Morgan, Bradley P, Murray, John C, Salter, Eben D, Wessel, Matthew D, Yocum, Sue A
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.03.2009
Amer Chemical Soc
Subjects
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Chemistry, Medicinal
Chromatography, High Pressure Liquid
Crystallography, X-Ray
Drug Discovery
Hormones. Endocrine system
Life Sciences & Biomedicine
Mass Spectrometry
Medical sciences
Models, Molecular
Pharmacology & Pharmacy
Pharmacology. Drug treatments
Phenanthrenes - chemistry
Phenanthrenes - pharmacology
Receptors, Glucocorticoid - agonists
Science & Technology
ALPHA
LIGAND-BINDING DOMAIN
MODEL
EFFICACY
MODULATORS
IN-VIVO
Agonist
Diol
Phenanthrene derivatives
Structure activity relation
Molecular model
Glucocorticoid receptor
Binding site
Chemical synthesis
In vitro
Modeling
Pyridine derivatives
Hormonal receptor
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Summary:As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or “dissociated” agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm801512v