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

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.Partial financial support from the “Ministerio de Ciencia e Innovación”, Spain (Project CTQ2008-01426/BQU), and “Generalitat de Catalunya” (Grant 2009SGR-1072) is acknowledged. L.D. is grateful to CSIC for predoctoral research training support within the JAE-Predoc program. The authors thank Dr. Meritxell Egido-Gabas for technical assistance, Núria Guillem and Laura Planas for experimental contributions, Eva Dalmau for HRMS analysis, and Genzyme Corp. for a generous supply of imiglucerase (Cerezyme). Finally, the authors acknowledge the “Centre de Supercomputació de Catalunya” (CESCA) for allowing the use of its software and hardware resources.Peer reviewe