Inhibitor of phospholipase A2 blocks eicosanoid and platelet activating factor biosynthesis and has topical anti-inflammatory activity.
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.
Tramposch
K M
KM
Dermatology Discovery Research, Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, New York.
Chilton
F H
FH
Stanley
P L
PL
Franson
R C
RC
Havens
M B
MB
Nettleton
D O
DO
Davern
L B
LB
Darling
I M
IM
Bonney
R J
RJ
D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D003872:Dermatitis / Q000378:metabolism / Q000517:prevention & control; D015777:Eicosanoids / Q000096:biosynthesis*; D006801:Humans; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D015777:Eicosanoids; D010972:Platelet Activating Factor; C078415:13-cis-12-(3'-carboxyphenyl)retinoic acid; D016718:Arachidonic Acid; D014212:Tretinoin; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate