Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: Indoline-Based Sulfamide Derivatives with Low Lipophilicity and Protein Binding Ratio
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- Takahashi Kenji
- Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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- Ohta Masaru
- Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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- Shoji Yoshimichi
- Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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- Kasai Masayasu
- Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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- Kunishiro Kazuyoshi
- Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.
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- Miike Tomohiro
- 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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To find a novel acyl-CoA: cholesterol acyltransferase inhibitor, a series of sulfamide derivatives were synthesized and evaluated. Compound 1d, in which carboxymethyl moiety at the 5-position of Pactimibe was replaced by a sulfamoylamino group, showed 150-fold more potent anti-foam cell formation activity (IC50: 0.02 μM), 1.6-fold higher log D7.0 (4.63), and a slightly lower protein binding ratio (93.2%) than Pactimibe. Compound 1i, in which the octyl chain at the 1-position in 1d was replaced by an ethoxyethyl, showed markedly low log D7.0 (1.73) and maintained 3-fold higher anti-foam cell formation activity (IC50: 1.0 μM), than Pactimibe. The plasma protein binding ratio (PBR) of 1i was much lower than that of Pactimibe (62.5% vs. 98.1%), and its partition ratio to the rabbit atherosclerotic aorta after oral administration was higher than that of Pactimibe. Compound 1i at 10 μM markedly inhibited cholesterol esterification in atherosclerotic rabbit aortas even when incubated with serum, while Pactimibe had little effect probably due to its high PBR. In conclusion, compound 1i is expected to more efficiently inhibit the progression of atherosclerosis than Pactimibe.
収録刊行物
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- CHEMICAL & PHARMACEUTICAL BULLETIN
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CHEMICAL & PHARMACEUTICAL BULLETIN 58 (8), 1057-1065, 2010
公益社団法人 日本薬学会
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詳細情報 詳細情報について
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- CRID
- 1390001204173131136
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- NII論文ID
- 130000299815
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- NII書誌ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL書誌ID
- 10764115
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- 本文言語コード
- en
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- データソース種別
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- JaLC
- NDL
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