Synthesis and Evaluation of 6-Nitro-7-(1-piperazino) quinazolines: Dual-Acting Compounds with Inhibitory Activities toward Both Tumor Necrosis Factor-α (TNF-α) Production and T Cell Proliferation
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概要
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We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C (4)-position with several N-alkyl groups to increase the lipophilicity at the C (4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-α (TNF-α) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-α production with an ED_<50> value of 26mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-α production in vivo as well as oral bioavailability.
- 公益社団法人日本薬学会の論文
- 2003-09-01
著者
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Negishi Toru
Research Division Sumitomo Pharmaceuticals Co. Ltd.
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Hayashi H
Univ. Tokyo Tokyo Jpn
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Tobe M
Sumitomo Pharmaceuticals Co. Ltd. Osaka Jpn
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Tobe Masanori
Research Division Discovery Research Laboratories Ii Sumitomo Pharmaceuticals Co. Ltd.
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Hayashi H
Drug Research Division Dainippon Sumitomo Pharma Co. Ltd.
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Hayashi Hideya
Pharmaceuticals And Biotechnology Laboratory Japan Energy Corporation
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Hayashi H
Pharmaceuticals & Biotechnology Laboratory Japan Energy Corporation
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Isobe Y
Research Division Discovery Research Laboratories Ii Sumitomo Pharmaceuticals Co. Ltd.
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Isobe Y
Sumitomo Pharmaceuticals Co. Ltd. Osaka Jpn
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Isobe Yoshiaki
Research Division Discovery Research Laboratories Ii Sumitomo Pharmaceuticals Co. Ltd.
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TOMIZAWA Hideyuki
Research Division, Sumitomo Pharmaceuticals Co., Ltd.
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NAGASAKI Takahiro
Research Division, Sumitomo Pharmaceuticals Co., Ltd.
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AOKI Masamitsu
Research Division, Sumitomo Pharmaceuticals Co., Ltd.
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HAYASHI Hideya
Research Division, Sumitomo Pharmaceuticals Co., Ltd.
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Isobe Y
Pharmaceuticals And Biotechnology Laboratory Japan Energy Corporation
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五十部 穣
Research Center Sumitomo Pharmaceuticals Co. Ltd.
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Aoki M
Research Division Sumitomo Pharmaceuticals Co. Ltd.
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NEGISHI Tomoe
Faculty of Pharmaceutical Sciences, Okayama University
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Negishi T
Faculty Of Pharmaceutical Sciences Okayama University
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Tomizawa Hideyuki
Research Division Sumitomo Pharmaceuticals Co. Ltd.
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