5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE, 1, Fig. 1) is the most potent eosinophil chemotactic factor among lipid mediators. Its actions are mediated by the selective oxoeicosanoid (OXE) receptor. Its potent effects on eosinophil migration suggest that it may play a crucial role in allergic asthma, one of the hallmarks of which is eosinophil infiltration into the lungs, which is associated with airway narrowing and remodeling. For these reasons, the OXE receptor is an attractive therapeutic target for the treatment of allergic asthma. We previously designed and synthesized the first and only series of indole based OXE receptor antagonists, S230 and S264 (Fig. 1), with potencies below 10 nM. Both S230 and S264 appear rapidly in blood after oral administration in cynomologus monkeys. However, their levels decease due to the metabolism of the hexyl side chain. To reduce the extent of metabolism, we modified the hexyl side chain by adding electron withdrawing and bulky groups. In some cases, we also varied the number of methylene units in between the indole ring and ω-carbon. These structural modifications resulted in a “second generation” OXE receptor antagonists with potencies upto 120 pM, and significantly reduced metabolism. The structure-activity relationship of the “second generation” antagonists and pharmacokinetics of the selected antagonists will be presented. These OXE receptor antagonists could provide a novel therapy for the treatment of asthma and other eosinophilic diseases.

Second generation oxoeicosanoid receptor antagonists: Increased potency and improved pharmacokinetics

255th National Meeting (2018)

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