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Inhibitor of phospholipase A2 blocks eicosanoid and platelet activating factor biosynthesis and has topical anti-inflammatory activity.

Abstract
The effect of a phospholipase A2 (PLA2) inhibitor on leukotriene, prostaglandin and platelet activating factor (PAF) biosynthesis in isolated cells and in vivo was determined. BMS-181162, [4(3'-carboxyphenyl)-3,7-dimethyl-9(2",6",6"-trimethyl-1"- cyclohexenyl)2Z,4E,6E,8E-nonatetraenoic acid], reversibly inhibited the 14-kdalton PLA2 purified from human synovial fluid with an IC50 of 8 microns. In A23187-stimulated human polymorphonuclear leukocytes (PMNs), BMS-181162 blocked arachidonic acid release with an IC50 of 10 microns. Leukotriene B4 and PAF biosynthesis in these cells was also inhibited. In a phorbol ester-induced chronic mouse skin inflammation model, topically applied BMS-181162 markedly lowered the tissue levels of leukotriene B4 and prostaglandin E2 and dose-dependently inhibited leukocyte infiltration (ED50 = 180 micrograms per ear). BMS-181162 is an inhibitor of PLA2 and may prove to be a useful tool in the delineation of the role of PLA2 in the inflammatory process.
AuthorsK M Tramposch, F H Chilton, P L Stanley, R C Franson, M B Havens, D O Nettleton, L B Davern, I M Darling, R J Bonney
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 271 Issue 2 Pg. 852-9 (Nov 1994) ISSN: 0022-3565 [Print] United States
PMID7965805 (Publication Type: Journal Article)
Chemical References
  • Anti-Inflammatory Agents
  • Eicosanoids
  • Platelet Activating Factor
  • 13-cis-12-(3'-carboxyphenyl)retinoic acid
  • Arachidonic Acid
  • Tretinoin
  • Phospholipases A
  • Phospholipases A2
  • Tetradecanoylphorbol Acetate
Topics
  • Administration, Topical
  • Anti-Inflammatory Agents (pharmacology)
  • Arachidonic Acid (metabolism)
  • Dermatitis (metabolism, prevention & control)
  • Eicosanoids (biosynthesis)
  • Humans
  • Neutrophils (drug effects, metabolism)
  • Phospholipases A (antagonists & inhibitors)
  • Phospholipases A2
  • Platelet Activating Factor (biosynthesis)
  • Tetradecanoylphorbol Acetate (pharmacology)
  • Tretinoin (analogs & derivatives, pharmacology)

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