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