Substituted phenyl as a steroid A-ring mimetic: Providing agonist activity to a class of arylsulfonamide nonsteroidal glucocorticoid ligands

A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6645-6649
Main Authors: DiSalvo, Darren, Kuzmich, Daniel, Bentzien, Jörg, Regan, John, Kukulka, Alison, Fadra-Khan, Tazmeen, Nelson, Richard, Harcken, Christian, Thomson, David, Nabozny, Gerald
Format: Article
Language:English
Subjects:
agonists
antagonists
Arylsulfonamide
Binding Sites
Glucocorticoid receptor
Glucocorticoid receptor agonist
Glucocorticoid receptors
Glucocorticoids
Glucocorticoids - chemistry
Hydrogen Bonding
Ligands
Mineralocorticoid receptor
Molecular Docking Simulation
Nuclear hormone receptor
Progesterone receptor
Protein Binding - drug effects
Protein Structure, Tertiary
Receptors, Glucocorticoid - agonists
Receptors, Glucocorticoid - metabolism
Steroids - chemistry
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - metabolism
Sulfonamides - pharmacology
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Summary:A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.10.047