Efficient Synthetic Method for Ethyl (+)-(2S,3S)-3-[(S)-3-Methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-oxiranecarboxylate (EST), a New Inhibitor of Cysteine Proteinases(Medicinal Chemistry,Chemical)
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概要
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Ethyl (+)-(2S,3S)-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-oxirane-carboxylate (EST; 1a) is expected to be useful as an oral therapeutic agent for muscular dystrophy on the basis of its potent inhibitory activities against the cysteine proteinases involved in the myofibrillar protein degradation that occurs in the disease. Through extensive investigations aimed at developing a new synthetic method for 1a that would be suitable for industrial application, it has been found that L-arginine can be used as a new, efficient resolving agent to obtain optically pure L-Znms-epoxysuccinic acid (3a), and the active ester method using p-nitrophenol is very effective in the coupling reaction.of ethyl L-trans-epoxysuccinate (7a) and L-leucine isoamylamide (8a) because of the extremely low formation of by-products. To examine the contribution of the stereochemistry of the trans-epoxysuccinic acid and leucine moieties to the inhibitory activity against cysteine proteinases, the diastereomers (1b-d) of la were synthesized by a similar method and the rate constants of inactivation of papain by 1a-d were measured. Compound 1a, having L-trans-epoxysuccinic acid and L-leucine moieties, showed the most potent activity among them.
- 1987-03-25
著者
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曾田 馨
Research Center, Taisho Pharmaceutical Co., Ltd.
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金岡 祐一
Faculty of Pharmaceutical Sciences, Hokkaido University
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金岡 裕一
Faculty Of Pharmaceutical Sciences Hokkaido University
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村田 充男
Research Center, Taisho Pharmaceutical Co., Ltd.,
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横尾 千尋
Research Center, Taisho Pharmaceutical Co., Ltd.,
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玉井 正晴
Research Center, Taisho Pharmaceutical Co., Ltd.,
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佐藤 英助
Faculty of Pharmaceutical Sciences, Hokkaido University
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佐藤 英助
Faculty Of Pharmaceutical Sciences Hokkaido University:(present Address)department Of Technology Aom
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玉井 正晴
Research Center Taisho Pharmaceutical Co. Ltd.
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村田 充男
Research Center Taisho Pharmaceutical Co. Ltd.
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横尾 千尋
Research Center Taisho Pharmaceutical Co. Ltd.
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小熊 清司
Research Center, Taisho Pharmaceutical Co., Ltd.
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曾田 馨
Research Center Taisho Pharmaceutical Co. Ltd.
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小熊 清司
Research Center Taisho Pharmaceutical Co. Ltd.
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