Late-breaking abstract: Preclinical evaluation of an inhibitor of cytosolic phospholipase A ₂ α for the treatment of asthma

Asthma is an inflammatory lung disease with considerable requirement for new and effective therapies. Cytosolic phospholipase A 2 α (cPLA 2 α) is the rate-limiting enzyme responsible for production of eicosanoids implicated in asthma. We investigated a novel cPLA 2 α inhibitor, PF-5212372, to establish the preclinical rationale for asthma. PF-5212372 potently and effectively inhibited prostaglandin D 2 (PGD 2 ) and cysteinyl leukotriene release from human lung mast cells (IC 50 s 0.29nM and 0.45nM, respectively). In a mixed human lung cell population, PF-5212372 effectively inhibited leukotriene B 4 , thromboxane A 2 and PGD 2 (IC 50 s 2.6nM, 2.6nM and 4.0nM, respectively), but was less effective against PGE 2 release (IC 50 >301nM, p <0.05). In an in vitro cell retention assay, PF-5212372 retained potency up to 24 h post wash-off. Inhaled PF-5212372 effectively inhibited late-phase bronchoconstriction (78% inhibition, p <0.001) and airway hyperresponsiveness (94% inhibition, p <0.001) in a sheep model of allergic asthma and demonstrated good sheep:human translation in sheep lung mast cells (PGD 2 IC 50 0.78nM). PF-5212372 was shown to inhibit AMP-induced constriction of ex vivo human bronchial sections (81% inhibition, p <0.01). PF-5212372 was safe and well tolerated in PhI studies. These data show that inhibition of cPLA 2 α using PF-5212372 is effective in a wide-range of pre-clinical asthma models and demonstrates cell retention that may yield clinical duration of action. PF-5212372 may represent a new therapeutic option for the treatment of asthma.