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)-5 H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro- N, N-dimethylbenzamide (BMS-776532) and its methylene homologue (BMS-791826)

David S. Weinstein, Hua Gong, Arthur M. Doweyko, Mark Cunningham, Sium Habte, Jin Hong Wang, Deborah A. Holloway, Christine Burke, Ling Gao, Victor Guarino, Julie Carman, John E. Somerville, David Shuster, Luisa Salter-Cid, John H. Dodd, Steven G. Nadler, Joel C. Barrish

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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.

Original languageEnglish (US)
Pages (from-to)7318-7333
Number of pages16
JournalJournal of Medicinal Chemistry
Volume54
Issue number20
DOIs
StatePublished - Oct 27 2011

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Weinstein, D. S., Gong, H., Doweyko, A. M., Cunningham, M., Habte, S., Wang, J. H., Holloway, D. A., Burke, C., Gao, L., Guarino, V., Carman, J., Somerville, J. E., Shuster, D., Salter-Cid, L., Dodd, J. H., Nadler, S. G., & Barrish, J. C. (2011). 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)-5 H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro- N, N-dimethylbenzamide (BMS-776532) and its methylene homologue (BMS-791826). Journal of Medicinal Chemistry, 54(20), 7318-7333. https://doi.org/10.1021/jm200879j