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

21 Citations (Scopus)

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
Pages (from-to)656-665
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume340
Issue number3
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

Fingerprint

Phospholipases A
Asthma
Prostaglandins D
Adenosine Monophosphate
Bronchi
Mast Cells
Lung
Sheep
Ionomycin
Leukotriene B4
Bronchoconstriction
Eicosanoids
Thromboxanes
Prostaglandins E
PF-5212372
varespladib methyl
Pharmaceutical Preparations
Inhalation
Lung Diseases
Inflammation

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 journalArticle

Hewson, CA, Patel, S, Calzetta, L, Campwala, H, Havard, S, Luscombe, E, Clarke, PA, Peachell, PT, Matera, MG, Cazzola, M, Page, C, Abraham, WM, Williams, CM, Clark, JD, Liu, WL, Clarke, NP & Yeadon, M 2012, 'Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α for the treatment of asthma', Journal of Pharmacology and Experimental Therapeutics, vol. 340, no. 3, pp. 656-665. https://doi.org/10.1124/jpet.111.186379
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. / Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α for the treatment of asthma. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 340, No. 3. pp. 656-665.
@article{03cb76511f86432da2ad90275e0271c7,
title = "Preclinical evaluation of an inhibitor of cytosolic phospholipase A 2α for the treatment of asthma",
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.",
author = "Hewson, {Christopher A.} and Sheena Patel and Luigino Calzetta and Hinnah Campwala and Suzanne Havard and Emma Luscombe and Clarke, {Philip A.} and Peachell, {Peter T.} and Matera, {Maria G.} and Mario Cazzola and Clive Page and Abraham, {William M.} and Williams, {Cara M.} and Clark, {James D.} and Liu, {Wai L.} and Clarke, {Nicholas P.} and Michael Yeadon",
year = "2012",
month = "3",
day = "1",
doi = "10.1124/jpet.111.186379",
language = "English",
volume = "340",
pages = "656--665",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84863150795&partnerID=8YFLogxK

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 -