5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is an arachidonic acid metabolite formed by the oxidation of the 5-lipoxygenase (5-LO) product 5S-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid). The high degree of selectivity of 5-HEDH suggested that 5-oxo-ETE might play an important pathophysiological role so we investigated its effects on various types of inflammatory cells and found that, among lipid mediators, it is the most powerful chemoattractant for human eosinophils. 5-HEDH is found in most types of inflammatory cells as well as various structural cells, and its activity is limited by the availability of the cofactor NADP+. Intradermal injection of 5-oxo-ETE in humans results in eosinophil infiltration into the skin, suggesting that it may be an important mediator in asthma and other diseases characterized by tissue eosinophilia. For this reason, in collaboration with Joshua Rokach (Florida Institute of Technology) we developed antagonists targeting the OXE receptor, which mediates the actions of 5-oxo-ETE, by adding substituents mimicking the a- and w- portions of 5-oxo-ETE to an indole scaffold. Screening of these compounds resulted in the identification of chiral compounds with IC50 values in low picomolar range and favorable pharmacokinetic properties, which we are currently testing in models of skin and airway inflammation in monkeys. Such antagonists may prove to be useful therapeutic agents for treating asthma in humans.
William Powell is a Professor in the Dept of Medicine at McGill University and is Associate Director of the Meakins-Christie Laboratories, which focuses on lung disease. After completing a PhD in organic chemistry at Dalhousie University he was introduced to the area of eicosanoids during a postdoctoral fellowship at the Karolinska Institute in Stockholm. His main research interests are in the role of eicosanoids in inflammation, in particular mediators that can induce eosinophil infiltration. He codiscovered the DP2 receptor, a second receptor for prostaglandin D2 that is highly expressed on eosinophils and promotes the migration of these cells into tissues. He also discovered a pathway resulting in the formation of the 5-lipoxygenase product 5-oxo-ETE and showed that this compound is a highly potent eosinophils chemoattractant. He is currently collaborating with Joshua Rokach of the Florida Institute of Technology to develop a 5-oxo-ETE antagonist that could potentially be useful in the treatment of asthma and other allergic diseases.