5 - Oxo - ETE A Novel Inflammatory Mediator

5-Oxo-ETE is the most potent chemotactic factor for eosinophils among lipid mediators. Also, it is a chemotactic factor for neutrophils and monocytes. It is formed by the action of a highly selective enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Its actions are mediated by the selective OXE receptor. Its potent effects on eosinophil migration suggest that it may play a role in allergic diseases such as asthma, one of the hallmarks of which is the infiltration of eosinophils into the lungs. Although these cells are important in host defense against parasites, their appearance in the lungs in asthma is associated with tissue damage, inflammation and airway narrowing. For these reasons, OXE receptor and 5-HEDH are attractive targets for drugs that could be useful in treating inflammatory diseases. The availability of such agents would also be invaluable in establishing the precise pathophysiological role of 5-oxo-ETE. Currently there are no known selective OXE receptor antagonists or 5-HEDH inhibitors. We have designed and synthesized two excellent OXE receptor antagonists active in the 6-9 nM range. We will develop a large-scale synthesis of our best antagonists, which can also be of general use and applied to the synthesis of other antagonists containing an asymmetric center. We will test select antagonists in a battery of assays, including an in vivo asthma model. We will also study the pharmacokinetics of these antagonists. In addition, we identified two selective inhibitors of 5-HEDH, active in the 0.2-0.3 µM range. Further modification of these compounds to the low nM range could lead to the development of useful therapeutic agents against asthma.

Our two OXE receptor antagonists, which are in an advanced stage of development, have the potential to generate in the very near future drugs with novel targets that could complement or replace the present-generation therapy. Current therapy relies on bronchodilators, steroids and, very recently, LTD4 antagonists, e.g. ‘Singulair’®, which I discovered while at Merck and Co., the most widely used prescription drug for asthma and allergic rhinitis.