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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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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Glucocorticoid Receptors
Pharmacology
Cytokines
Ligands
Halogenation
Prednisolone
Transcriptional Activation
Rodentia
Anti-Inflammatory Agents
Transcription Factors
N,N-dimethylbenzamide
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
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
Inflammation
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Weinstein, David S. ; Gong, Hua ; Doweyko, Arthur M. ; Cunningham, Mark ; Habte, Sium ; Wang, Jin Hong ; Holloway, Deborah A. ; Burke, Christine ; Gao, Ling ; Guarino, Victor ; Carman, Julie ; Somerville, John E. ; Shuster, David ; Salter-Cid, Luisa ; Dodd, John H. ; Nadler, Steven G. ; Barrish, Joel C. / 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). In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 20. pp. 7318-7333.
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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.",
author = "Weinstein, {David S.} and Hua Gong and Doweyko, {Arthur M.} and Mark Cunningham and Sium Habte and Wang, {Jin Hong} and Holloway, {Deborah A.} and Christine Burke and Ling Gao and Victor Guarino and Julie Carman and Somerville, {John E.} and David Shuster and Luisa Salter-Cid and Dodd, {John H.} and Nadler, {Steven G.} and Barrish, {Joel C.}",
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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 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, vol. 54, no. 20, pp. 7318-7333. https://doi.org/10.1021/jm200879j

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

In: Journal of Medicinal Chemistry, Vol. 54, No. 20, 27.10.2011, p. 7318-7333.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Azaxanthene based selective glucocorticoid receptor modulators

T2 - 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)

AU - Weinstein, David S.

AU - Gong, Hua

AU - Doweyko, Arthur M.

AU - Cunningham, Mark

AU - Habte, Sium

AU - Wang, Jin Hong

AU - Holloway, Deborah A.

AU - Burke, Christine

AU - Gao, Ling

AU - Guarino, Victor

AU - Carman, Julie

AU - Somerville, John E.

AU - Shuster, David

AU - Salter-Cid, Luisa

AU - Dodd, John H.

AU - Nadler, Steven G.

AU - Barrish, Joel C.

PY - 2011/10/27

Y1 - 2011/10/27

N2 - 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.

AB - 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.

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