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-6,8,11,14-eicosatetraenoic
acid (5-oxo-ETE) is a potent lipid
mediator that induces tissue eosinophilia 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 chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times
lower and a substantially longer plasma half-life. A single major
metabolite, which retains antagonist activity (IC50, 690
pM) and has a prolonged lifetime in plasma was observed. These new
highly potent OXE-R antagonists may provide a novel strategy for the
treatment of eosinophilic disorders like asthma.