Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Synthesis and Biological Evaluation of Quinuclidine Derivatives Incorporating Phenothiazine Moieties as Squalene Synthase Inhibitors
Tsukasa IshiharaHirotoshi KakutaHiroshi MoritaniTohru UgawaIsao Yanagisawa
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2004 Volume 52 Issue 10 Pages 1204-1209

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Abstract

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 IC50 value of 0.12 μM. 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.

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© 2004 The Pharmaceutical Society of Japan
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