Syntheses of 3-Ethylidenequinuclidine derivatives as squalene synthase inhibitors. Part 2: enzyme inhibition and effects on plasma lipid levels
| Autor: | Shuichi Sakamoto, Isao Yanagisawa, Tsukasa Ishihara, Hirotoshi Kakuta, Shin ichi Tsukamoto, Hiroshi Moritani, Tohru Ugawa |
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| Rok vydání: | 2003 |
| Předmět: |
Quinuclidines
Stereochemistry Hydrochloride Guinea Pigs Clinical Biochemistry Carbazoles Administration Oral Pharmaceutical Science Biochemistry Transaminase chemistry.chemical_compound Squalene Cricetinae Microsomes Drug Discovery Animals Humans Enzyme Inhibitors Molecular Biology Pravastatin chemistry.chemical_classification Farnesyl-diphosphate farnesyltransferase biology ATP synthase Cholesterol Cholesterol HDL Organic Chemistry Lipids Rats Farnesyl-Diphosphate Farnesyltransferase Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 11:3735-3745 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/s0968-0896(03)00336-5 |
| Popis: | 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 9 H -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]-9 H -carbazole hydrochloride 8 (YM-53579) and ( E )-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9 H -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. |
| Databáze: | OpenAIRE |
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