Novel 3-oxa lipoxin A4 analogues with enhanced chemical and metabolic stability have anti-inflammatory activity in vivo.
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.
Guilford
William J
WJ
Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, USA. william_guilford@berlex.com
Bauman
John G
JG
Skuballa
Werner
W
Bauer
Shawn
S
Wei
Guo Ping
GP
Davey
David
D
Schaefer
Caralee
C
Mallari
Cornell
C
Terkelsen
Jennifer
J
Tseng
Jih-Lie
JL
Shen
Jun
J
Subramanyam
Babu
B
Schottelius
Arndt J
AJ
Parkinson
John F
JF
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
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