Lipoxin A4 (
LXA4) and
aspirin-triggered
15-epi-LXA4 are structurally and functionally distinct
eicosanoids, with potent anti-inflammatory and immunomodulatory actions.
Therapeutic use of
LXA4 is greatly limited by its rapid metabolism in vivo and chemical instability. First-generation synthetic
LXA4 analogs such as methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), were designed to minimize metabolism from the omega-end of the molecule. Pharmacokinetic analysis of ATLa revealed beta-oxidation as a novel route for
LXA4 metabolism, prompting the development of second-generation 3-oxa-LXA4 analogs with improved pharmacokinetic disposition. Second-generation 3-oxa-LXA4 analogs such as (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoic
acid (3), have shown potency and efficacy comparable to ATLa in diverse animal models after topical, intravenous or oral delivery. These include several acute (2-24 h) inflammatory reactions:
calcium ionophore-induced skin
edema and
inflammation (topical),
LTB4/
PGE2-induced skin
inflammation and vascular leak (topical),
zymosan A-induced
peritonitis (i.v. and oral) and
ischemia-reperfusion-induced secondary organ injury (i.v.). Remarkably, 3-oxa-LXA4 analogs have potent once daily oral efficacy in preventing and promoting the resolution of established
colitis induced by the
hapten trinitrobenzene sulphonic
acid (TNBS), an acute/chronic 7-14-day model of
Crohn's disease. The second-generation 3-oxa-LXA4 analogs thus provide new stable pharmacophores with which to explore the emerging role of
lipoxins as a new therapeutic principle for regulating
inflammation,
allergy and immune dysfunction in preclinical and clinical research.