Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Discovery of a Potent and Orally Available Acyl-CoA: Cholesterol Acyltransferase Inhibitor as an Anti-atherosclerotic Agent: (4-Phenylcoumarin)acetanilide Derivatives
Masaki OginoSeiji FukuiYoshihisa NakadaRyosuke TokunohShigekazu ItokawaYuichi KakoiSatoshi NishimuraTsukasa SanadaHiromitsu FuseKazuki KuboTakeo WadaShogo Marui
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2011 Volume 59 Issue 10 Pages 1268-1273

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Abstract

Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme that catalyzes cholesterol esterification. ACAT inhibitors are expected to be potent therapeutic agents for the treatment of atherosclerosis. A series of potent ACAT inhibitors based on an (4-phenylcoumarin)acetanilide scaffold was identified. Evaluation of the structure–activity relationships of a substituent on this scaffold, with an emphasis on improving the pharmacokinetic profile led to the discovery of 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (23), which exhibited potent ACAT inhibitory activity (IC50=12 nM) and good pharmacokinetic profile in mice. Compound 23 also showed regressive effects on atherosclerotic plaques in apolipoprotein (apo)E knock out (KO) mice at a dose of 0.3 mg/kg per os (p.o.).

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© 2011 The Pharmaceutical Society of Japan
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