4-Alkoxybenzamidines as new potent phospholipase A2 inhibitors.
A series of 4-alkoxybenzamidines was synthesized, varying the number of carbons of the alkyl chain, and their potency as phospholipase A2 (PLA2) inhibitors was evaluated. The relationship between their capacity to inhibit PLA2 activity and their lipophilicity was examined. The optimum of the inhibitory effect against two extracellular PLA2S from rabbit platelets and bovine pancreas was observed with compounds bearing an alkyl chain of 12 and 14 carbons. These 4-dodecyl and tetradecyloxbenzamidines inhibited bovine pancreatic and rabbit platelet lysate PLA2S with IC50 values of 3 microM and 5-5.8 microM, respectively. The mechanism of inhibition was of the competitive type. In addition, 4-tetradecyloxbenzamidine was shown to exert an antiinflammatory effect in vivo on the carrageenan-induced rat paw oedema. These results show that 4-tetradecyloxybenzamidine will serve as an interesting tool to investigate the physiological role of mammalian-secreted PLA2, both in vitro and in vivo.
Aitdafoun
M
M
Laboratorire De Pharacochimie Moléculaire, Universite Paris, France.
Mounier
C
C
Heymans
F
F
Binisti
C
C
Bon
C
C
Godfroid
J J
JJ
D000208:Acute Disease; D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002351:Carrageenan; D002417:Cattle; D002908:Chronic Disease; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D007700:Kinetics; D008297:Male; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate
D001550:Benzamidines; D004791:Enzyme Inhibitors; D002351:Carrageenan; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate