Ishihara Tsukasa, Kakuta Hirotoshi, Moritani Hiroshi, Ugawa Tohru, Yanagisawa Isao
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 2004 Oct;52(10):1204-9. doi: 10.1248/cpb.52.1204.
Squalene synthase inhibitors have the potential to be superior hypocholesterolemic agents. A series of quinuclidine derivatives incorporating phenothiazine systems was synthesized in order to investigate the effects of their structure on the inhibition of hamster liver microsomal enzyme. (+/-)-3-(10-Methyl-10H-phenothiazin-3-ylmethoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC(50) value of 0.12 microM. Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels. Compound 19 showed a reduced tendency to elevate plasma transaminase levels, an indicator of hepatotoxicity. Enantiomerically pure (-)-19, YM-53546, was found to be more potent than the corresponding (+)-enantiomer.
角鲨烯合酶抑制剂有潜力成为更优质的降胆固醇药物。为了研究其结构对仓鼠肝微粒体酶抑制作用的影响，合成了一系列含有吩噻嗪体系的奎宁环衍生物。（±）-3-（10-甲基-10H-吩噻嗪-3-基甲氧基）奎宁环盐酸盐（19）是该系列中最有效的抑制剂，IC50值为0.12微摩尔。给仓鼠口服化合物19可有效降低血浆总胆固醇水平和血浆甘油三酯水平。化合物19升高血浆转氨酶水平（肝毒性指标）的趋势有所降低。发现对映体纯的（-）-19，即YM-53546，比相应的（+）-对映体更有效。
