Bioavailable Acyl-CoA : Cholesterol Acyltransferase Inhibitor with Anti-peroxidative Activity : Synthesis and Biological Activity of Novel Indolinyl Amide and Urea Derivatives
スポンサーリンク
概要
- 論文の詳細を見る
We synthesized a series of indoline derivatives with an amide or urea moiety and examined their inhibitory effects on acyl-CoA : cholesterol acyltransferase (ACAT) activity, lipid-peroxidation and serum cholesterol levels in experimental animals. Among the derivatives synthesized, a series of N-(1-alkyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamides potently inhibited rabbit intestinal ACAT activity and lipid-peroxidation of rat brain homogenate. The effect on ACAT activity was related to the length of the alkyl chain at the 1-position of indoline. N-(4,6-Dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide hydrochloride (55) showed inhibitory effects on intestinal and hepatic ACAT activity slightly weaker than those of YM-750,and an inhibitory effect on low density lipoprotein (LDL)-peroxidation similar to that of probucol. Compound 55 also reduced serum cholesterol at 10mg/kg/d in hyperlipidemic rats and 20 mg/kg/d in normolipidemic hamsters. The plasma concentration of 55 reached 716ng/ml in dogs (10mg/kg, p.o.), which is an effect concentration against hepatic ACAT activity and LDL-peroxidation. In conclusion, compound 55 is a novel bioavailable ACAT inhibitor with anti-peroxidative activity and is thus a promising anti-atherosclerotic and anti-hyperlipidemic drug. Indoline proved to be a useful pharmacophore for molecular design of new anti-peroxidative drugs.
- 公益社団法人日本薬学会の論文
- 2000-06-01
著者
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NAKAMURA Seikou
Kyoto Pharmaceutical University
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中村 紳一郎
Specialty Chemicals Research Center Shin-etsu Chemical Co. Ltd.
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Takahashi K
Faculty Of Pharmaceutical Sciences Hoshi University
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Nakamura S
Toyama Univ. Toyama Jpn
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Takahashi K
School Of Pharmaceutical Sciences Kitasato University
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Nakamura S
Specialty Chemicals Research Center Shin-etsu Chemical Co. Ltd.
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Takahashi Kenji
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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Kasai Masayasu
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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Kanda Mamoru
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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Shirahase Hiroaki
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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MATSUI Hiroshi
Research Institute for Scientific Measurements, Tohoku University
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Kanda Mamoru
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Nakamura Satoko
Osaka University Of Pharmaceutical Sciences
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Narimatsu Shizuo
Laboratories Of Health Chemistry Graduate School Of Medicine Dentistry And Pharmaceutical Sciences O
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Shirahase Hiroaki
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Shirahase Hiroaki
Research Laboratories Kyoto Pharmaceutical Company Ltd.
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Kurahashi Kazuyoshi
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Kunishiro Kazuyoshi
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Kamiya Shoji
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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NAKAMURA Shohei
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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YOSHIMI Akihisa
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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KURAHASHI Kazuyoshi
Pharmacology Division, Radioisotope Research Center, Kyoto University
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Kamiya S
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Nakamura Shohei
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Kanda M
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Yoshimi A
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Narimatsu Shizuo
Department Of Hygienic Chemistry Faculty Of Pharmaceutical Sciences Hokuriku University
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Shirahase H
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Nakamura S
Laboratories Of Health Chemistry Graduate School Of Medicine Dentistry And Pharmaceutical Sciences O
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Yoshimi Akihisa
Research Laboratories Kyoto Pharmaceutical Industries Ltd.
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Kurahashi Kazuyoshi
Pharmacology Division Radioisotope Research Center And Department Of Pharmacology Faculty Of Medicin
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Matsui H
Yamaguchi Univ. Hospital Ube Jpn
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Matsui Hiroshi
Research Institute For Scientific Measurements
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Takahashi Kenji
Research And Development Group Japan Energy Corporation
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Kasai Masayasu
Research Laboratories, Kyoto Pharmaceutical Industries
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