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Research ArticleInflammation, Immunopharmacology, and Asthma

Preclinical Evaluation of an Inhibitor of Cytosolic Phospholipase A2α for the Treatment of Asthma

Christopher A. Hewson, Sheena Patel, Luigino Calzetta, Hinnah Campwala, Suzanne Havard, Emma Luscombe, Philip A. Clarke, Peter T. Peachell, Maria G. Matera, Mario Cazzola, Clive Page, William M. Abraham, Cara M. Williams, James D. Clark, Wai L. Liu, Nicholas P. Clarke and Michael Yeadon
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 656-665; DOI: https://doi.org/10.1124/jpet.111.186379
Christopher A. Hewson
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Sheena Patel
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Luigino Calzetta
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Hinnah Campwala
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Suzanne Havard
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Emma Luscombe
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Philip A. Clarke
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Peter T. Peachell
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Maria G. Matera
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Mario Cazzola
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Clive Page
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William M. Abraham
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Cara M. Williams
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James D. Clark
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Wai L. Liu
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Nicholas P. Clarke
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Michael Yeadon
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Abstract

Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A2α (cPLA2α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA2α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA2α (7 nM) and was able to inhibit prostaglandin (PG)D2 and cysteinyl leukotriene release from anti-IgE-stimulated human lung mast cells (0.29 and 0.45 nM, respectively). In a mixed human lung cell population, PF-5212372 was able to inhibit ionomycin-stimulated release of leukotriene B4, thromboxane A2, and PGD2 (2.6, 2.6, and 4.0 nM, respectively) but was significantly less effective against PGE2 release (>301 nM; p < 0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h after being washed off. In a sheep model of allergic inflammation, inhalation of PF-5212372 significantly inhibited late-phase bronchoconstriction (78% inhibition; p < 0.001) and airway hyper-responsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD2 release (0.78 nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchi induced by AMP. PF5212372 significantly inhibited AMP-induced contraction of human bronchi (81% inhibition; p < 0.001); this finding, together with the ability of this drug to be effective in a wide range of preclinical asthma models, suggests that inhibition of cPLA2α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.

Footnotes

  • This work was funded by Pfizer Ltd.

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

    http://dx.doi.org/10.1124/jpet.111.186379.

  • ABBREVIATIONS:

    cPLA2α
    cytosolic phospholipase A2α
    AHR
    airway hyper-responsiveness
    AUC
    area under the concentration-time curve
    COX
    cyclooxygenase
    CRTH2
    chemoattractant receptor expressed on T helper type 2 cells
    DPI
    dry powder inhaler
    ELISA
    enzyme-linked immunosorbent assay
    FA
    formic acid
    FCS
    fetal calf serum
    GLU
    7-hydroxycoumarinyl-γ-linolenate
    LT
    leukotriene
    PBS
    phosphate-buffered saline
    PG
    prostaglandin
    TX
    thromboxane
    HPLC
    high-performance liquid chromatography
    MOX
    methoximated
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    MK 571
    (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid.

  • Received July 27, 2011.
  • Accepted December 6, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleInflammation, Immunopharmacology, and Asthma

cPLA2α for Treatment of Asthma

Christopher A. Hewson, Sheena Patel, Luigino Calzetta, Hinnah Campwala, Suzanne Havard, Emma Luscombe, Philip A. Clarke, Peter T. Peachell, Maria G. Matera, Mario Cazzola, Clive Page, William M. Abraham, Cara M. Williams, James D. Clark, Wai L. Liu, Nicholas P. Clarke and Michael Yeadon
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 656-665; DOI: https://doi.org/10.1124/jpet.111.186379

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Research ArticleInflammation, Immunopharmacology, and Asthma

cPLA2α for Treatment of Asthma

Christopher A. Hewson, Sheena Patel, Luigino Calzetta, Hinnah Campwala, Suzanne Havard, Emma Luscombe, Philip A. Clarke, Peter T. Peachell, Maria G. Matera, Mario Cazzola, Clive Page, William M. Abraham, Cara M. Williams, James D. Clark, Wai L. Liu, Nicholas P. Clarke and Michael Yeadon
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 656-665; DOI: https://doi.org/10.1124/jpet.111.186379
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