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YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species.

Abstract：

:The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and fibrates, respectively. YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED(50), 32 mg kg(-1)). In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol - high density lipoprotein cholesterol) by 47% (P<0.001) and 33% (P<0.001), respectively (100 mg kg(-1), daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg(-1), twice daily for 21 days, P<0.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg(-1), twice daily for 28 days). YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg(-1), daily for 5 days, P<0.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P<0.001) was superior to that of fenofibrate (by 53%, P<0.001), the most potent fibrate (dosage of each drug: 100 mg kg(-1), daily for 7 days). This is the first report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a fibrate in significantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Ugawa T,Kakuta H,Moritani H,Matsuda K,Ishihara T,Yamaguchi M,Naganuma S,Iizumi Y,Shikama H

doi

10.1038/sj.bjp.0703545

subject

Has Abstract

pub_date

2000-09-01 00:00:00

pages

63-70

issue

1

eissn

0007-1188

issn

1476-5381

journal_volume

131

pub_type

杂志文章

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