Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors

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概要

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• 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-yl-methoxy)quinuclidine hydrochloride (19) was the most potent inhibitor in this series with an IC_<50> value of 0.12μм. 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.

• 公益社団法人日本薬学会の論文
• 2004-10-01

著者

• UGAWA Tohru

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

• Ugawa Tohru

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Yanagisawa Isao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• ISHIHARA Tsukasa

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd.

• KAKUTA Hirotoshi

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd.

• MORITANI Hiroshi

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd.

• Kakuta Hirotoshi

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Ishihara Tsukasa

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Moritani Hiroshi

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

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