title: Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α 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(2)α (cPLA(2)α) 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(2)α inhibitor, PF-5212372, to establish the potential of this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (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 hyper-responsiveness (94% inhibition; p < 0.001), and isolated sheep lung mast cell assays confirmed species translation via effective inhibition of PGD(2) release (0.78 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(2)α with PF-5212372 may represent a new therapeutic option for the treatment of asthma.
authors.affiliation: Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Sandwich, United Kingdom. c_hewson@sky.com
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hewson
authors.forename: Sheena
authors.initials: S
authors.lastname: Patel
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.forename: Hinnah
authors.initials: H
authors.lastname: Campwala
authors.forename: Suzanne
authors.initials: S
authors.lastname: Havard
authors.forename: Emma
authors.initials: E
authors.lastname: Luscombe
authors.forename: Philip A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Peter T
authors.initials: PT
authors.lastname: Peachell
authors.forename: Maria G
authors.initials: MG
authors.lastname: Matera
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Clive
authors.initials: C
authors.lastname: Page
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Cara M
authors.initials: CM
authors.lastname: Williams
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.forename: Wai L
authors.initials: WL
authors.lastname: Liu
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clarke
authors.forename: Michael
authors.initials: M
authors.lastname: Yeadon
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy*; D016084:Bronchoconstriction / Q000187:drug effects; D061207:Calcium Ionophores / Q000494:pharmacology; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D006801:Humans; D008407:Mast Cells / Q000502:physiology; D010666:Phenylpropionates / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000378:metabolism; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061207:Calcium Ionophores; D004791:Enzyme Inhibitors; C571285:PF-5212372; D010666:Phenylpropionates; D013449:Sulfonamides; C026408:anti-IgE antibodies; D054513:Group IV Phospholipases A2; D015230:Prostaglandin D2