5-Oxo-ETE, which acts via the G-protein-coupled OXE receptor (OXE-R), is the most potent eosinophil chemoattractant among lipid mediators. We postulated that a selective OXE-R antagonist (none of which were available) might be a useful therapeutic agent in asthma. To test this hypothesis, we prepared selective OXE-R antagonists, which, with the support of the AAF, we modified to a series of “2nd generation” antagonists, culminating in S3, which has low picomolar in vitro potency and excellent pharmacokinetic properties. Unlike our earlier antagonists, which are extensively metabolized, S3 is converted to a single major plasma metabolite, which is as active in vitro as S3. With help from the AAF, Lisa Miller at UC Davis, and the venture capital company AmorChem, we have completed skin and lung studies in monkeys that have generated a large number of samples. Encouraged by the preliminary data, in the coming year we plan to analyze these samples and extend our in vivo experiments, which we hope will pave the way for future clinical studies. The specific aims of the present study are to: 1)Complete the analysis of samples generated from our aerosol challenge study designed to determine whether S3 can inhibit allergen-induced airway inflammation, including soluble markers in BAL fluid, eosinophils and neutrophils in lung tissue, and tissue and plasma levels of S3. 2)Perform additional preclinical studies to pave the way for future clinical trials, including a dose-response study on allergen-induced dermal inflammation and toxicology testing. 3)Perform the total synthesis and pharmacokinetics of the main S3 metabolite (α-hydroxy-S3).