An Inhibitor of Cholesterol Synthesis

In contrast with ML-236B, CS-514, a new derivative of ML-236B, showed tissue-specific inhibition of sterol synthesis, selectively in liver and intestine, the major sites of cholesterogenesis. In freshly-isolated rat hepatocytes and in the cell-free enzyme system from rat liver, concentrations required for 50% inhibition were 2.2ng/ml and 0.8ng/ml, respectively, corresponding to one-third and onetenth to those of ML-236B. On the other hand, inhibition of sterol synthesis was negligible in rat peripheral tissues such as hormone-producing organs or cultured cells such as human skin fibroblasts. By using 14C-CS-514, it was found that tissue specificity of the inhibition was attributed to difference of cell uptake of the compound.CS-514 significantly reduced serum cholesterol levels in dogs, monkeys, rabbits, WHHL-rabbits and Triton-induced hyperlipidemic rats and also preferentially reduced serum lipoproteins in all the animals tested so far. CS-514 caused no significant changes in the syntheses of fatty acids, proteins, DNA, RNA, and ketone bodies.Hypocholesterolemic effect of CS-514 in WHHL-rabbit, an animal model for familial hypercholesterolemia (FH) in man, suggests hypolipidemic action of the compound in FH.