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.

• Authors: William J Guilford, John G Bauman, Werner Skuballa, Shawn Bauer, Guo Ping Wei, David Davey, Caralee Schaefer, Cornell Mallari, Jennifer Terkelsen, Jih-Lie Tseng, Jun Shen, Babu Subramanyam, Arndt J Schottelius, John F Parkinson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 8 Pg. 2157-65 (Apr 08 2004) ISSN: 0022-2623 [Print] United States
• PMID: 15056011 (Publication Type: Journal Article)

Chemical References

• 16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoic acid
• 16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,13-hexadecatrien-11-ynoic acid
• Anti-Inflammatory Agents, Non-Steroidal
• Ionophores
• Lipoxins
• Phenyl Ethers
• lipoxin A4
• Calcimycin

Topics

• Acute Disease
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, metabolism, pharmacology)
• Calcimycin
• Dermatitis, Contact (drug therapy, etiology)
• Drug Stability
• Ionophores
• Lipoxins (chemical synthesis, metabolism, pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Oxidation-Reduction
• Phenyl Ethers (chemical synthesis, metabolism, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship