Click chemistry approach to new N-substituted aminocyclitols as potential pharmacological chaperones for Gaucher disease.

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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

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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