Novel inhibitor of phospholipase A2 with topical anti-inflammatory activity.
Activation of a phospholipase A2 (PLA2) is a key step in the production of precursors for the biosynthesis of lipid mediators of inflammation. Inhibition of this enzyme could result in the suppression of three important classes of inflammatory lipids, prostaglandins, leukotrienes and platelet activating factor (PAF), and offers an attractive therapeutic approach to design novel agents for the treatment of inflammation and tissue injury. In this report we describe a novel compound, BMS-181162 4(3'-carboxyphenyl)-3,7-dimethyl-9(2",6"6"-trimethyl-1"-cyclohexenyl),++ +2Z,4E,6E, 8E-nonatetraenoic acid which specifically inhibits a 14 kD human PLA2 and effectively blocks phorbol ester induced skin inflammation in mice. BMS-181162 is the first reported specific inhibitor of PLA2 and its specificity may make useful tool in the dissection 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 14213.
Steiner
S A
SA
Stanley
P L
PL
Nettleton
D O
DO
Franson
R C
RC
Lewin
A H
AH
Carroll
F I
FI
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D051379:Mice; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000097:blood / Q000302:isolation & purification; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C078415:13-cis-12-(3'-carboxyphenyl)retinoic acid; D014212:Tretinoin; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate