S-12340 - A POTENT INHIBITOR OF THE OXIDATIVE MODIFICATION OF LOW-DENSITY-LIPOPROTEIN IN-VITRO AND EX-VIVO IN WHHL RABBITS

Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation a nd progression of the atherosclerotic plaque. After evaluation of a la rge number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidat ive modification induced either by copper ions or by cultured endothel ial cells. Both the electrophoretic mobility and the thiobarbituric ac id reactive substances returned to almost normal values in the presenc e of 0.5 mu M of S 12340. Watanabe heritable hyperlipidemic rabbits we re treated orally for 3 days or for 1 month with S 12340 to evaluate t he potential protective effect of the compound on LDL oxidative modifi cation induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to prote ct 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 admi nistration 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 WHH L rabbits. S 12340, probucol and vitamin E were all able to decrease t he optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demo nstrating their free radical scavenging properties. The pharmacologica l properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.