Novel highly potent and metabolically resistant oxoeicosanoid (OXE) receptor antagonists that block the actions of the granulocyte chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE).

5-Oxo-6,8 ,ll,14-eicosatetraenoic aci5-oS-oxo-ETE) is a potent lipid mediator that induces tissue eosinolihiha via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side cha.ins Compared with our previous lead compound S-230, our most potent antagonisS-, SC025, has an(50)C(S0) (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (50C 0), 690 pM) and has a prolonged lifetime in plasma was obser.ved These new highly potent OXER antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma.