5-Oxo-ETE has the qualifications of an important physiological mediator: It is formed by a highly selective enzyme 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Its actions are mediated by the selective OXE receptor (OXE-R), and metabolism by various pathways results in its biological inactivation. Its potent effects on eosinophils suggest that it may play a role in allergic diseases such as asthma. One of the hallmarks of this disease is the accumulation of eosinophils in the lungs. Although these cells are important in host defense against parasites, their appearance in the lungs in asthma is associated with tissue damage and inflammation. Because of 5-oxo-ETE's proliferative effects on tumor cells it could also be involved in cancer. For these reasons, OXE-R and 5-HEDH are attractive targets for drugs that could be useful for the treatment of inflammatory diseases and cancer. The availability of such agents would also be invaluable in establishing the precise pathophysiological role of 5-oxo-ETE. Currently there are no selective OXE receptor antagonists or 5- HEDH inhibitors, and this is further complicated by the lack of a mouse model due to the absence of OXE-R in this species. In this application we propose to design and synthesize both an OXE receptor antagonist and a 5-HEDH inhibitor and evaluate these compounds in vitro and in vivo. We will develop reagents that will provide critical information about the localization and regulation of 5-HEDH. This includes the synthesis of 5- HETE affinity chromatography ligands for 5-HEDH purification, followed by sequencing and cloning of the enzyme. This would enable the generation of antibodies for immunocytochemistry and primers for PCR. With the aid of minimum energy model we developed for 5-oxo-ETE, we have already made good progress in identifying conformationally restricted synthetic antagonists. We also identified two selective inhibitors of 5- HEDH. Further modification of these compounds could lead to the development of useful therapeutic agents. A successful conclusion could have important therapeutic implications in asthma and other inflammatory diseases. Because of the proliferative effect of 5-oxo-ETE on tumor cells, such drugs could also be useful in cancer therapy. This application has the potential of generating drugs with novel targets that could complement or replace the present generation therapy, which relies on bronchodilators, steroids and, very recently, LTD4 antagonists, e.g. """"""""Singulair""""""""(R), the most widely used prescription drug for asthma and allergic rhinitis. Unfortunately, with this recent success, the pharmaceutical companies have stopped their research for next-generation asthma therapy. A novel approach as described in this application may be timely.
One of the hallmarks of asthma is the accumulation of white blood cells (eosinophils) in the lungs during the onset of an asthma attack. It is likely that these eosinophils are responsible for late phase asthma or inflammatory asthma. We plan to develop agents that will stop the infiltration of these cells into the lung and prevent inflammatory asthma.
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