New glucocerebrosidase inhibitors by exploration of chemical diversity of N-substituted aminocyclitols using click chemistry and in situ screening.

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Diaz L, Casas J, Bujons J, Llebaria A, Delgado A

New glucocerebrosidase inhibitors by exploration of chemical diversity of N-substituted aminocyclitols using click chemistry and in situ screening.

J Med Chem. 2011 Apr 14;54(7):2069-79. doi: 10.1021/jm101204u. Epub 2011 Mar 3.

PubMed ID

21370884 [ View in PubMed

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Abstract

A library of aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1-25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aqueous system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually resynthesized for further biological screening and complete characterization. Some of the library members have shown biochemical data (IC(50), K(i), and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand-enzyme interactions to account for the experimental results.

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