Click chemistry approach to new N-substituted aminocyclitols as potential pharmacological chaperones for Gaucher disease.
Article Details
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Diaz L, Bujons J, Casas J, Llebaria A, Delgado A
Click chemistry approach to new N-substituted aminocyclitols as potential pharmacological chaperones for Gaucher disease.
J Med Chem. 2010 Jul 22;53(14):5248-55. doi: 10.1021/jm100198t.
- PubMed ID
- 20557054 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) (2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOL Glucosylceramidase Ki (nM) 300 N/A N/A Details (2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOL Glucosylceramidase IC 50 (nM) 300 N/A N/A Details (2R,3R,4R,5S)-2-(HYDROXYMETHYL)-1-NONYLPIPERIDINE-3,4,5-TRIOL Glucosylceramidase IC 50 (nM) 660 N/A N/A Details