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 language | English |
|---|---|
| Pages (from-to) | 656-665 |
| Number of pages | 10 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 340 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Pharmacology
- Molecular Medicine
Cite this
Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α for the treatment of asthma. / Hewson, Christopher A.; Patel, Sheena; Calzetta, Luigino; Campwala, Hinnah; Havard, Suzanne; Luscombe, Emma; Clarke, Philip A.; Peachell, Peter T.; Matera, Maria G.; Cazzola, Mario; Page, Clive; Abraham, William M.; Williams, Cara M.; Clark, James D.; Liu, Wai L.; Clarke, Nicholas P.; Yeadon, Michael.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 340, No. 3, 01.03.2012, p. 656-665.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α for the treatment of asthma
AU - Hewson, Christopher A.
AU - Patel, Sheena
AU - Calzetta, Luigino
AU - Campwala, Hinnah
AU - Havard, Suzanne
AU - Luscombe, Emma
AU - Clarke, Philip A.
AU - Peachell, Peter T.
AU - Matera, Maria G.
AU - Cazzola, Mario
AU - Page, Clive
AU - Abraham, William M.
AU - Williams, Cara M.
AU - Clark, James D.
AU - Liu, Wai L.
AU - Clarke, Nicholas P.
AU - Yeadon, Michael
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84863150795&partnerID=8YFLogxK
U2 - 10.1124/jpet.111.186379
DO - 10.1124/jpet.111.186379
M3 - Article
C2 - 22160268
AN - SCOPUS:84863150795
VL - 340
SP - 656
EP - 665
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -