Nonsteroidal Dissociated Glucocorticoid Agonists Containing Azaindoles as Steroid A-Ring Mimetics

Syntheses and structure−activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen indu...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-09, Vol.53 (18), p.6681-6698
Main Authors: Riether, Doris, Harcken, Christian, Razavi, Hossein, Kuzmich, Daniel, Gilmore, Thomas, Bentzien, Jörg, Pack, Edward J, Souza, Donald, Nelson, Richard M, Kukulka, Alison, Fadra, Tazmeen N, Zuvela-Jelaska, Ljiljana, Pelletier, Josephine, Dinallo, Roger, Panzenbeck, Mark, Torcellini, Carol, Nabozny, Gerald H, Thomson, David S
Format: Article
Language:English
Subjects:
Adipose Tissue - drug effects
Animals
Anti-Inflammatory Agents, Non-Steroidal - adverse effects
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Aromatase - biosynthesis
Aromatase - genetics
Aromatase Inhibitors - pharmacology
Arthritis, Experimental - drug therapy
Biological Availability
Cells, Cultured
Enzyme Induction
Female
Humans
Hydrogen Bonding
Insulin - blood
Interleukin-1 - pharmacology
Interleukin-6 - antagonists & inhibitors
Interleukin-6 - biosynthesis
Interleukin-6 - genetics
Mice
Mice, Inbred BALB C
Models, Molecular
Pyridines - adverse effects
Pyridines - chemical synthesis
Pyridines - pharmacology
Pyrroles - adverse effects
Pyrroles - chemical synthesis
Pyrroles - pharmacology
Rats
Rats, Sprague-Dawley
Receptors, Glucocorticoid - agonists
Stereoisomerism
Steroids - chemistry
Structure-Activity Relationship
Transcriptional Activation
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Description
Summary:Syntheses and structure−activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds ( R )-16 and ( R )-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100751q