Shoichiro Goto and Teruhiko Shimokawa
Cardiovascular & Atherosclerosis Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan
Abstract: YM-16638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)
propyl]thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid) showed a strong hypocholesterolemic effect in humans and monkeys. To clarify the mechanism of this hypocholesterolemic effect, the action of YM-16638 on cholesterol biosynthesis in the cultured human hepatoma cell line HepG2 and cynomolgus monkey liver was examined. Cholesterol biosynthesis activity derived from [14C]acetic acid, [3H/14C]mevalonic acid or [14C]isopentenyl pyrophosphate substrates was significantly decreased, but not that from [3H]farnesyl pyrophosphate or [3H]squalene substrates in HepG2 cells treated with YM-16638. Simultaneously, treatment of these cells with YM-16638 changed neither the rate of apolipoprotein B synthesis from [35S]methionine nor its secretion. In addition, the activities of hepatic cholesterol biosynthesis enzymes HMG-CoA reductase, mevalonate kinase (MK), isopentenyl pyrophosphate isomerase (IPPI), farnesyl pyrophosphate synthase (FPPS), squalene synthase and squalene epoxidase were measured in monkeys fed a diet supplemented with YM-16638. Among these enzymes, MK, IPPI and FPPS activities in the YM-16638-treated group significantly decreased by 38%, 56% and 30%, respectively, when compared to those from control animals receiving no drug treatment. These results indicate that YM-16638 has the characteristics of a cholesterol biosynthesis inhibitor.
Keywords: Cholesterol biosynthesis enzyme, Cynomolgus monkey, HepG2 cell, Hypocholesterolemic effect, YM-16638