Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α for the treatment of asthma

Asthma is a chronic inflammatory lung disease with considerable unmet medical requirement for new and effective therapies. Cytosolic phospholipase A(2)α (cPLA(2)α) is the rate-limiting enzyme ultimately responsible for production of eicosanoids implicated in the pathophysiology of asthma. We investigated a novel cPLA(2)α inhibitor, PF-5212372, to establish the potential for this drug as a treatment for asthma. PF-5212372 was a potent inhibitor of cPLA(2)α (7nM) and was able to inhibit prostaglandin D(2) (PGD(2)) and cysteinyl leukotriene release from anti-IgE stimulated human lung mast-cells (0.29nM and 0.45nM, 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) (2.6nM, 2.6nM and 4.0nM, respectively), but was significantly less effective against prostaglandin E(2) (>301nM, p<0.05). In an in vitro cell retention assay, PF-5212372 retained its potency up to 24 h post wash-off. In a sheep model of allergic asthma, 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 (0.78nM). Finally, PF-5212372 was assessed for its ability to inhibit the contraction of human bronchus induced by adenosine 5-monophosphate (AMP). PF-5212372 significantly inhibited AMP induced contraction of human bronchus (81% inhibition, p<0.001) and along with the ability of this drug to be effective in a wide-range of pre-clinical asthma models, suggests that inhibition of cPLA(2)α using PF-5212372 may represent a new therapeutic option for the treatment of asthma.