S 12340: a potent inhibitor of the oxidative modification of low- density lipoprotein in vitro and ex vivo in WHHL rabbits

C Breugnot, S Privat, C Guillonneau, G Regnier, F Bouzom, JP Vilaine and A Lenaers

Institut de Recherches Servier-92150 Suresnes, France.

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.

Volume 269, Issue 2, pp. 515-520, 05/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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