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.
MeSH terms
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Alkaline Phosphatase / biosynthesis
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Arthritis, Experimental / drug therapy
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Cell Line, Tumor
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Drug Partial Agonism
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Edema / drug therapy
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Glutamate-Ammonia Ligase / biosynthesis
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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In Vitro Techniques
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Interleukin-1beta / blood
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Male
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Models, Molecular
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Rats
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Rats, Inbred Lew
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Rats, Sprague-Dawley
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Receptors, Glucocorticoid / agonists*
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Receptors, Glucocorticoid / genetics
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Receptors, Glucocorticoid / metabolism
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Response Elements
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Stereoisomerism
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis*
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacology
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transcriptional Activation
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Tumor Necrosis Factor-alpha / blood
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Tyrosine Transaminase / biosynthesis
Substances
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2-(4-((dimethylamino)carbonyl)-3-fluorophenyl)-alpha,alpha-dimethyl-N-1,3,4-thiadiazol-2-yl-5H-(1)benzopyrano(2,3-b)pyridin-5-acetamide
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5-2-(4-((ethylmethylamino)carbonyl)-3-fluorophenyl)-alpha,alpha-dimethyl-N-1,3,4-thiadiazol-2-yl-5H-(1)benzopyrano(2,3-b)pyridin-5-acetamide
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Anti-Inflammatory Agents, Non-Steroidal
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Heterocyclic Compounds, 3-Ring
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Interleukin-1beta
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Receptors, Glucocorticoid
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Thiadiazoles
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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Tyrosine Transaminase
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Alkaline Phosphatase
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Glutamate-Ammonia Ligase