Abstract
The hypolipidemic properties of KCD-232(4-(4'-chlorobenzyloxy) benzyl nicotinate), a new compound, were studied in rats fed a basal diet and mice fed a high-cholesterol diet with the following results: 1) KCD-232 reduced serum cholesterol (CH), triglyceride (TG) and phospholipid (PL) levels in a dose-dependent manner (20-160 mg/kg/day) in rats fasted for 16 hr. 2) KCD-232 significantly reduced (LDL+VLDL)-CH and decreased the (LDL+VLDL)-CH/HDL-CH ratio designated as the “atherogenic index” unlike clofibrate which was used as a reference. 3) KCD-232 slightly increased relative liver weight, but not in the dose-dependent manner of clofibrate. 4) KCD-232 also inhibited the elevation of serum CH level in mice fed a high-cholesterol diet in a dose-dependent manner, and this inhibitory effect was more pronounced than those of clofibrate and nicotinic acid (NA). 5) Liver CH and fatty acid (FA) synthesis from [1-14C] acetate were inhibited both in vitro and in vivo in rats orally administered KCD-232. Clofibrate also decreased CH synthesis, whereas it increased FA synthesis. NA had no effect on either synthesis. 6) After oral administration of [4-14C] cholesterol to rats that were cannulated into the thoracic-duct lymph, KCD-232 markedly depressed the appearance of "C-cholesterol in lymph. 7) KCD-232 induced no proliferation of hepatic peroxisomes in rats, unlike clofibrate. The detailed hypolipidemic mechanism of KCD-232 is not yet clear, but as shown, it decreased CH synthesis in the liver, exogenous CH absorption from the intestine and FA synthesis in the liver. These results suggest that the serum lipid-lowering profiles of KCD-232 differ from those of clofibrate and NA.
