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).

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Citation

Weinstein DS, Gong H, Doweyko AM, Cunningham M, Habte S, Wang JH, Holloway DA, Burke C, Gao L, Guarino V, Carman J, Somerville JE, Shuster D, Salter-Cid L, Dodd JH, Nadler SG, Barrish JC

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).

J Med Chem. 2011 Oct 27;54(20):7318-33. doi: 10.1021/jm200879j. Epub 2011 Oct 3.

PubMed ID
21899328 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PrednisoloneGlucocorticoid receptorKi (nM)1.5N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)14.4N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)73.9N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)16.1N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)64N/AN/ADetails
PrednisoloneGlucocorticoid receptorEC 50 (nM)21N/AN/ADetails