Targeting the OXE receptor as a potential novel therapy for asthma.

5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid metabolite formed by oxidation of the 5-lipoxygenase (5-LO) product 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5S-HETE) by the NADP-dependent enzyme 5-hydroxyeicosanoid dehydrogenase. It is the only 5-LO product with appreciable chemoattractant activity for human eosinophils. Its actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, basophils, neutrophils and monocytes. Orthologs of the OXER1 gene, which encodes this receptor, are found in many species except for rodents. Intradermal injection of 5-oxo-ETE into humans and monkeys elicits eosinophil infiltration into the skin, raising the possibility that it may play a pathophysiological role in eosinophilic diseases. To investigate this and possibly identify a novel therapy we sought to prepare synthetic antagonists that could selectively block the OXE receptor. We synthesized a series of indole-based compounds bearing substituents that mimic the regions of 5-oxo-ETE that are required for biological activity, which we modified to reduce metabolism. The most potent of these OXE receptor antagonists is S-Y048, which is a potent inhibitor of 5-oxo-ETE-induced calcium mobilization (IC, 20 pM) and has a long half-life following oral administration. S-Y048 inhibited allergen-induced eosinophil infiltration into the skin of rhesus monkeys that had been experimentally sensitized to house dust mite and inhibited pulmonary inflammation resulting from challenge with aerosolized allergen. These data provide the first evidence for a pathophysiological role for 5-oxo-ETE in mammals and suggest that potent and selective OXE receptor antagonists such as S-Y048 may be useful therapeutic agents in asthma and other eosinophilic diseases.