TY - JOUR T1 - Preclinical Evaluation of an Inhibitor of Cytosolic Phospholipase A<sub>2</sub>α for the Treatment of Asthma JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 656 LP - 665 DO - 10.1124/jpet.111.186379 VL - 340 IS - 3 AU - Christopher A. Hewson AU - Sheena Patel AU - Luigino Calzetta AU - Hinnah Campwala AU - Suzanne Havard AU - Emma Luscombe AU - Philip A. Clarke AU - Peter T. Peachell AU - Maria G. Matera AU - Mario Cazzola AU - Clive Page AU - William M. Abraham AU - Cara M. Williams AU - James D. Clark AU - Wai L. Liu AU - Nicholas P. Clarke AU - Michael Yeadon Y1 - 2012/03/01 UR - http://jpet.aspetjournals.org/content/340/3/656.abstract N2 - 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 (&gt;301 nM; p &lt; 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 &lt; 0.001) and airway hyper-responsiveness (94% inhibition; p &lt; 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 &lt; 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. ER -