Second-generation beta-oxidation resistant 3-oxa-lipoxin A4 analogs.
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.
Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA. william_guilford@berlex.com
William J
WJ
Guilford
John F
JF
Parkinson
D000284:Administration, Oral; D000818:Animals; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D044045:Lipoxins / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction
D044045:Lipoxins; C040527:lipoxin A4