title: 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.affiliation: Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA. william_guilford@berlex.com
authors.forename: William J
authors.initials: WJ
authors.lastname: Guilford
authors.forename: John G
authors.initials: JG
authors.lastname: Bauman
authors.forename: Werner
authors.initials: W
authors.lastname: Skuballa
authors.forename: Shawn
authors.initials: S
authors.lastname: Bauer
authors.forename: Guo Ping
authors.initials: GP
authors.lastname: Wei
authors.forename: David
authors.initials: D
authors.lastname: Davey
authors.forename: Caralee
authors.initials: C
authors.lastname: Schaefer
authors.forename: Cornell
authors.initials: C
authors.lastname: Mallari
authors.forename: Jennifer
authors.initials: J
authors.lastname: Terkelsen
authors.forename: Jih-Lie
authors.initials: JL
authors.lastname: Tseng
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Arndt J
authors.initials: AJ
authors.lastname: Schottelius
authors.forename: John F
authors.initials: JF
authors.lastname: Parkinson
mesh_terms: D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000001:Calcimycin; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000209:etiology; D004355:Drug Stability; D007476:Ionophores; D044045:Lipoxins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C485114:16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoic acid; C485115:16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,13-hexadecatrien-11-ynoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007476:Ionophores; D044045:Lipoxins; D010647:Phenyl Ethers; C040527:lipoxin A4; D000001:Calcimycin