Journal
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS
Volume 73, Issue 3-4, Pages 245-250Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.plefa.2005.05.012
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Lipoxin A(4) (LXA(4)) and aspirin-triggered 15-epi-LXA(4) are structurally and functionally distinct eicosanoids, with potent anti-inflammatory and immunomodulatory actions. Therapeutic use of LXA(4) is greatly limited by its rapid metabolism in vivo and chemical instability. First generation synthetic LXA(4) 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 LXA(4) metabolism, prompting the development of second-generation 3-oxa-LXA(4) analogs with improved pharmacokinetic disposition. Second-generation 3-oxa-LXA(4) analogs such as (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluoropheiioxy)-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 (2-24h) inflammatory reactions: calcium ionophore-induced skin edema and inflammation (topical), LTB4/PGE(2)-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. (c) 2005 Elsevier Ltd. All rights reserved.
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