Novel 3-Oxa Lipoxin A<INF>4</INF> Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Lipoxin A<INF>4</INF> (LXA<INF>4</INF>) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA<INF>4</INF>, methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (<BO>2</BO>, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, <BO>3</BO>, was improved over <BO>2</BO> without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both <BO>2</BO> and <BO>3</BO> identified a previously undetected metabolite, which is consistent with metabolism by β-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, <BO>4</BO>, and the 3-oxatrien-11-yne, <BO>5</BO>, analogues of <BO>2</BO>. Evaluation of 3-oxa analogues <BO>4</BO> and <BO>5</BO> in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to <BO>2</BO>. The 3-oxatrien-11-yne analogue, <BO>5</BO>, is equipotent to <BO>2</BO> in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.