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.
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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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