title: 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.
authors.affiliation: Cardiovascular Diseases Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. ugawa@yamanouchi.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Ugawa
authors.forename: H
authors.initials: H
authors.lastname: Kakuta
authors.forename: H
authors.initials: H
authors.lastname: Moritani
authors.forename: K
authors.initials: K
authors.lastname: Matsuda
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: M
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Naganuma
authors.forename: Y
authors.initials: Y
authors.lastname: Iizumi
authors.forename: H
authors.initials: H
authors.lastname: Shikama
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D006224:Cricetinae; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008253:Macaca mulatta; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D014280:Triglycerides / Q000097:blood*
chemical_list: D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D011812:Quinuclidines; D014280:Triglycerides; C414830:YM 53601; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase