Novel Malonamide Derivatives as α_vβ_3 Antagonists.Syntheses and Evaluation of 3-(3-Indolin-1-yl-3-oxopropanoyl)aminopropanoic Acids on Vitronectin Interaction with α_vβ_3
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概要
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In attempt to find novel integrin α_vβ_3 antagonists, we selected SC65811 and its guanidine analogue (1) as lead compounds. Modification of the glycine part of SC65811 led to a new series of malonamide derivatives that exhibited α_vβ_3 inhibitory activity. Among them, (R, S)-3-{3-[6-(3-benzylureido)indolin-1-yl]-3-oxopropanoylamino}-3-(pyridin-3-yl)propanoic acid (43a) showed not only potent activity with an IC_<50> value of 3.0nM but also good selectivity for α_vβ_3 relative to α_<IIb>β_3, α_5β_1, and α_vβ_5 with IC_<50> values of 19000, 11000, and 14nM, respectively. Furthermore, optimization of 43a led to the most potent α_vβ_3 antagonist, (R, S)-3-(3-{6-[(4, 5-dihydro-1H-imidazol-2-yl)amino]indolin-1-yl}-3-oxopropanoylamino)-3-(quinolin-3-yl)propanoic acid (431) with an IC_<50> value of 0.42nM. The synthesis and the structure-activity relationships of these malonamide derivatives are presented.
- 公益社団法人日本薬学会の論文
- 2001-11-01
著者
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Suzuki K
Astellas Research Service Co. Ltd. Astellas Pharma Inc.
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SUZUKI Ken-ichi
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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AKAMATSU Seijiro
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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Suzuki K
Noda Research Laboratories Drug Delivery System Institute Ltd.:(present Address)pharmaceutics Resear
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Okada M
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.ltd.
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Suzuki Ken-ichi
Astellas Research Service Co. Ltd. Astellas Pharma Inc.
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Akamatsu Seijiro
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.ltd.
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Akamatsu Seijiro
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.:(present Address)drug Disco
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Okada Minoru
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Suzuki K
Molecular Imaging Center National Institute Of Radiological Sciences
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TSUKAMOTO Shin-ichi
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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Matsumoto Yuzo
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.ltd.
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Kawaminami Eiji
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.ltd.
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NAGASHIMA Shinya
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co.Ltd.,
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Nagashima S
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.ltd.
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Suzuki Ken-ichi
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Tsukamoto S
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.ltd.
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Tsukamoto Shin-ichi
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Matsumoto Y
Hoshi Univ. Tokyo Jpn
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