CHOLESTEROL-LOWERING EFFECT OF YM-16638 IN CYNOMOLGUS MONKEYS

YM-16638 was found in preclinical studies to be an orally active leuko triene antagonist. Because LY-171883, another leukotriene receptor ant agonist with a similar structure to YM-16638, showed a triglyceride-lo wering effect with a peroxisomal proliferative effect in monkeys fed a normal diet, we investigated whether YM-16638 also showed a serum tri glyceride-lowering effect by examining serum and hepatic lipid levels in cynomolgus monkeys fed a normal diet supplemented with YM-16638 for 4 weeks at a daily dose of 3.75 mg (8.5 mu mole), 30 mg (67.7 mu mole ) or 60 mg (135.4 mu mole)/kg body weight. Monkeys given YM-16638 show ed a dose-dependent decrease in serum total cholesterol. At 2 weeks of treat ment, serum LDL- and HDL-cholesterol in the YM-16638 group show ed marked decreases of 35% and 32%, respectively. However, serum trigl yceride levels did not change, By contrast, hepatic cholesterol and ch olesterol ester levels in this group were only slightly increased, wit hout any effect on hepatic triglyceride level. In vitro investigation of the effect of YM-16638 on LDL-receptor activity and mRNA expression in the human hepatoma cell line HepG2 cells showed that YM-16638 incr eased LDL-receptor activity in a dose-dependent manner at 44 h of trea tment. mRNA level in these cells was also increased 1.7-fold at 8 h of treatment. These results suggest that the decrease in serum cholester ol level in monkeys treated with YM-16638 may be due to an increase in hepatic LDL-receptor activity. Furthermore, they suggest that YM-1663 8 may represent a potent hypocholesterolemic drug without serious side effects. (C) 1996 Wiley-Liss, Inc.