| Autor: |
Weinstein DS; Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States. David.Weinstein@bms.com, 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 |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2011 Oct 27; Vol. 54 (20), pp. 7318-33. Date of Electronic Publication: 2011 Oct 03. |
| DOI: |
10.1021/jm200879j |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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