Click Chemistry Approach to New N-Substituted Aminocyclitols as Potential Pharmacological Chaperones for Gaucher Disease

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• 作者：Luca Daz ; Jordi Bujons ; Josefina Casas ; Amadeu Llebaria ; Antonio Delgado
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 22, 2010
• 年：2010
• 卷：53
• 期：14
• 页码：5248-5255
• 全文大小：1091K
• 年卷期：v.53,no.14(July 22, 2010)
• ISSN：1520-4804

文摘

New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain have been prepared as potential GCase pharmacological chaperones using click chemistry approaches. Among them, compounds 1d and 1e, with the shorter spacer (n = 1) between the alkyltriazolyl system and the aminocyclitol core, were the most active ones as GCase inhibitors, revealing a determinant effect of the location of the triazole ring on the activity. Furthermore, SAR data and computational docking models indicate a correlation between lipophilicity and enzyme inhibition and suggest “extended” and “bent” potential binding modes for the compounds. In the “bent” mode, the most active compounds could establish a hydrogen-bond interaction between the triazole moiety and enzyme residue Q284. Such an interaction would be precluded in compounds with a longer spacer between the triazole and the aminocyclitol core.