Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α 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, Michael Yeadon

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Asthma is a chronic inflammatory lung disease with considerable unmet medical needs for new and effective therapies. Cytosolic phospholipase A 2α (cPLA 2α) is the rate-limiting enzyme that is ultimately responsible for the production of eicosanoids implicated in the pathogenesis of asthma. We investigated a novel cPLA 2α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA 2α (7 nM) and was able to inhibit prostaglandin (PG)D 2 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 B 4, thromboxane A 2, and PGD 2 (2.6, 2.6, and 4.0 nM, respectively) but was significantly less effective against PGE 2 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 hyperresponsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD 2 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 cPLA 2α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.

Original languageEnglish (US)
Pages (from-to)656-665
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume340
Issue number3
DOIs
StatePublished - Mar 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Hewson, C. A., Patel, S., Calzetta, L., Campwala, H., Havard, S., Luscombe, E., Clarke, P. A., Peachell, P. T., Matera, M. G., Cazzola, M., Page, C., Abraham, W. M., Williams, C. M., Clark, J. D., Liu, W. L., Clarke, N. P., & Yeadon, M. (2012). Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α for the treatment of asthma. Journal of Pharmacology and Experimental Therapeutics, 340(3), 656-665. https://doi.org/10.1124/jpet.111.186379