Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Abstract

Lipoxin A(4) (LXA(4)) 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(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, 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, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.

A β-oxidation-resistant lipoxin A4analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction

“…Recently, ␤-oxidation at C2-C3 was identified as a route for ATL analog metabolism in vivo, prompting design of ␤-oxidation-resistant 3-oxa-ATL analogs, including a 3-oxa-trienyne analog with enhanced chemical stability and oral pharmacokinetics (ZK-192, Fig. 1), which had topical antiinflammatory activity in skin (10). Here, we describe the oral efficacy profile and mechanism of action of ZK-192 in rodent TNBS colitis.…”

Lipoxin A4 inhibits immune cell binding to salivary epithelium and vascular endothelium

“…Thus, LXA 4 regulates functions that promote inflammatory resolution in many systems in vivo and in vitro (79). The LXA 4 antiinflammatory effects have been observed in a variety of inflammatory diseases including asthma (56), dermal inflammation (41), and arthritis (28). It has been reported that the oral administration of an LXA 4 analog attenuated dextran sulfate sodium-induced colitis (37) and that the oral delivery of another LXA 4 analog (3-oxa-ATL analog ZK-192) exhibited antiinflammatory effects on a 2,4,6-trinitrobenzene sulfonic acid-induced colitis model (33).…”

Development and Application of an Automated Solution Stability Assay for Drug Discovery

“…Compounds are tested in physiological buffers and gastrointestinal fluids to maximize oral bioavailability. [7][8][9][10][11] At the stage of development of parenteral formulations, the development candidates need to possess good stability and compatibility with different excipients in the formulated solutions to be successful in the clinic. 12,13 Another important application of solution stability is prodrug screening, in which large numbers of prodrugs are tested in different physiological fluids to select the candidate with the most desirable properties.…”