title: Syntheses of 3-ethylidenequinuclidine derivatives as squalene synthase inhibitors. Part 2: enzyme inhibition and effects on plasma lipid levels.
abstract: Squalene synthase (E.C. 2.5.1.21) is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene, and is involved in the first committed step in cholesterol biosynthesis. It is an attractive target for hypocholesterolemic and hypotriglyceridemic strategies. We synthesized a series of 3-ethylidenequinuclidine derivatives, and evaluated their ability to inhibit squalene synthase in vitro and to lower non-HDL cholesterol levels in hamsters. 3-Ethylidenequinuclidine derivatives incorporating an unsubstituted 9H-carbazole moiety reduced plasma non-HDL cholesterol levels and did not affect plasma transaminase levels, indicating a lack of hepatotoxicity. Among the novel compounds, (Z)-2-[2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 8 (YM-53579) and (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 28 (YM-53601) were potent inhibitors of squalene synthase derived from human hepatoma cells, with IC(50) values of 160 and 79 nM, respectively. They also reduced plasma non-HDL cholesterol levels in hamsters by approximately 50 and 70%, respectively, at an oral dose of 50 mg/kg/day for 5 days.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21Miyukigaoka, Tsukuba, 305-8585, Ibaraki, Japan. ishihat@yamanouchi.co.jp
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kakuta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moritani
authors.forename: Tohru
authors.initials: T
authors.lastname: Ugawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin ichi
authors.initials: Si
authors.lastname: Tsukamoto
authors.forename: Isao
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000032:analysis / Q000097:blood; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D006801:Humans; D008055:Lipids / Q000097:blood*; D008861:Microsomes / Q000201:enzymology; D017035:Pravastatin / Q000494:pharmacology; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats
chemical_list: D002227:Carbazoles; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D008055:Lipids; D011812:Quinuclidines; D013186:Farnesyl-Diphosphate Farnesyltransferase; D017035:Pravastatin