| Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α for the treatment of asthma. | |
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MedLine Citation:
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PMID: 22160268 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Asthma is a chronic inflammatory lung disease with considerable unmet medical requirement for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme ultimately responsible for production of eicosanoids implicated in the pathophysiology of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential for this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (7nM) and was able to inhibit prostaglandin D(2) (PGD(2)) and cysteinyl leukotriene release from anti-IgE stimulated human lung mast-cells (0.29nM and 0.45nM, 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) (2.6nM, 2.6nM and 4.0nM, respectively), but was significantly less effective against prostaglandin E(2) (>301nM, p<0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h post wash-off. In a sheep model of allergic asthma, 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 PGD(2) release (0.78nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchus induced by adenosine 5-monophosphate (AMP). PF-5212372 significantly inhibited AMP induced contraction of human bronchus (81% inhibition, p<0.001) and along with the ability of this drug to be effective in a wide-range of pre-clinical asthma models, suggests that inhibition of cPLA(2)α using PF-5212372 may represent a new therapeutic option for the treatment of asthma. |
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Authors:
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Christopher A Hewson; Sheena Patel; Luigino Calzetta; Hinnah Campwala; Suzanne Havard; Emma Luscombe; Philip A Clarke; Peter 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 |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-7 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: - ISSN: 1521-0103 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 Pfizer; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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