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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Benzothiophene Inhibitor of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Inhibits Tumor Necrosis Factor α Production and Has Oral Anti-Inflammatory Efficacy in Acute and Chronic Models of Inflammation

Robert J. Mourey, Barry L. Burnette, Sarah J. Brustkern, J. Scott Daniels, Jeffrey L. Hirsch, William F. Hood, Marvin J. Meyers, Stephen J. Mnich, Betsy S. Pierce, Matthew J. Saabye, John F. Schindler, Sarah A. South, Elizabeth G. Webb, Jian Zhang and David R. Anderson
Journal of Pharmacology and Experimental Therapeutics June 2010, 333 (3) 797-807; DOI: https://doi.org/10.1124/jpet.110.166173
Robert J. Mourey
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Barry L. Burnette
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Sarah J. Brustkern
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J. Scott Daniels
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Jeffrey L. Hirsch
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William F. Hood
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Marvin J. Meyers
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Stephen J. Mnich
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Betsy S. Pierce
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Matthew J. Saabye
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John F. Schindler
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Sarah A. South
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Elizabeth G. Webb
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Jian Zhang
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David R. Anderson
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Abstract

Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (Ki = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFα production with similar activity (IC50 = 160 nM). PF-3644022 blocks TNFα and IL-6 production in LPS-stimulated human whole blood with IC50 values of 1.6 and 10.3 μM, respectively. Inhibition of TNFα in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFα model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFα production in the acute model and inhibition of paw swelling in the chronic model is observed with ED50 values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a Cmin higher than the EC50 measured in the rat LPS-induced TNFα model.

Footnotes

  • This study was sponsored by Pfizer Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.166173.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    MAPK
    mitogen-activated protein kinase
    MAPKAP
    MAPK-activated protein
    MK2
    MAPKAP kinase 2
    MNK
    MAPK-interacting kinase
    PF-3644022
    (10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5′,6′:4,5]thieno[3,2-f]quinolin-8-one
    RA
    rheumatoid arthritis
    TNF
    tumor necrosis factor
    IL-1
    interleukin-1
    PRAK
    p38-regulated and activated kinase
    LPS
    lipopolysaccharide
    SCW
    streptococcal cell wall
    rSCW
    rat SCW
    MSK
    mitogen- and stress-activated protein kinase
    HSP27
    heat shock protein 27
    hPBMC
    human peripheral blood mononuclear cell
    HWB
    human whole blood
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    PK-PD
    pharmacokinetic-pharmacodynamic
    BE
    biochemical efficiency
    DMSO
    dimethyl sulfoxide
    JNK
    c-Jun N-terminal kinase
    ERK
    extracellular signal-regulated kinase
    AUC
    area under the curve
    CL
    clearance
    ff
    free fraction.

  • Received January 19, 2010.
  • Accepted March 16, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Benzothiophene Inhibitor of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Inhibits Tumor Necrosis Factor α Production and Has Oral Anti-Inflammatory Efficacy in Acute and Chronic Models of Inflammation

Robert J. Mourey, Barry L. Burnette, Sarah J. Brustkern, J. Scott Daniels, Jeffrey L. Hirsch, William F. Hood, Marvin J. Meyers, Stephen J. Mnich, Betsy S. Pierce, Matthew J. Saabye, John F. Schindler, Sarah A. South, Elizabeth G. Webb, Jian Zhang and David R. Anderson
Journal of Pharmacology and Experimental Therapeutics June 1, 2010, 333 (3) 797-807; DOI: https://doi.org/10.1124/jpet.110.166173

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

A Benzothiophene Inhibitor of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Inhibits Tumor Necrosis Factor α Production and Has Oral Anti-Inflammatory Efficacy in Acute and Chronic Models of Inflammation

Robert J. Mourey, Barry L. Burnette, Sarah J. Brustkern, J. Scott Daniels, Jeffrey L. Hirsch, William F. Hood, Marvin J. Meyers, Stephen J. Mnich, Betsy S. Pierce, Matthew J. Saabye, John F. Schindler, Sarah A. South, Elizabeth G. Webb, Jian Zhang and David R. Anderson
Journal of Pharmacology and Experimental Therapeutics June 1, 2010, 333 (3) 797-807; DOI: https://doi.org/10.1124/jpet.110.166173
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