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Azaxanthene Based Selective Glucocorticoid Receptor Modulators: Design, Synthesis, and Pharmacological Evaluation of (S)-4-(5-(1-((1,3,4-Thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro-N,N-dimethylbenzamide (BMS-776532) and Its Methylene Homologue (BMS-791826)
- Source :
- Journal of Medicinal Chemistry. 54:7318-7333
- Publication Year :
- 2011
- Publisher :
- American Chemical Society (ACS), 2011.
-
Abstract
- Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.
- Subjects :
- Male
Models, Molecular
Transcriptional Activation
Agonist
medicine.drug_class
Stereochemistry
Interleukin-1beta
Stereoisomerism
In Vitro Techniques
Response Elements
Partial agonist
Rats, Sprague-Dawley
Structure-Activity Relationship
Transactivation
Receptors, Glucocorticoid
Glucocorticoid receptor
Glutamate-Ammonia Ligase
Cell Line, Tumor
Thiadiazoles
Drug Discovery
medicine
Animals
Edema
Humans
Structure–activity relationship
Receptor
Tyrosine Transaminase
Transrepression
Tumor Necrosis Factor-alpha
Chemistry
Anti-Inflammatory Agents, Non-Steroidal
Alkaline Phosphatase
Arthritis, Experimental
Rats
Drug Partial Agonism
Transcription Factor AP-1
Rats, Inbred Lew
Molecular Medicine
Heterocyclic Compounds, 3-Ring
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 54
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....8940fbff21f4573dc814883881292e72