The infiltration of leukocytes into lung tissue and airways is a key feature of asthma, with high numbers of eosinophils observed in the airways; the number of eosinophils correlates with disease severity. 5-oxo-ETE is the most potent chemoattractant mediators known for eosinophils. Given these unique features of oxo-ETE, it is believed that an antagonist that would block this mediator could prevent eosinophilic infiltration in animal models of inflammation.
Such an inhibitor could potentially be useful either as stand-alone or in combination therapy for severe cases of asthma where eosinophilic infiltration is associated with exacerbations and tissue remodeling, in mild to moderate asthma, where it could complement well known therapies, or in disorders such as hyper-eosinophilic diseases, eosinophilic esophagitis and IBD.
We have identified 5-oxo-ETE inhibitors that have nanomolar activity in blocking 5-oxo-ETE-induced calcium mobilization, actin polymerisation and neutrophil migration. These molecules exhibited good PK properties in monkeys, and were further developed in our chemistry program such that we now have an enantiopure lead, S-025, with pM activity in the cellular assays. This lead molecule has good drug-like properties, is orally bioavailable, and is currently in testing in a non-human primate model of house dust mite-induced allergy/asthma.