Second-generation iminoxylitol-based pharmacological chaperones for the treatment of Gaucher disease.

A series of O-alkyl iminoxylitol derivatives was synthesized and evaluated as β-glucocerebrosidase (GCase) inhibitors. This structure-activity study shows a dramatic influence of the position of the alkyl chain (α-C1, O2, O3, or O4) on human GCase inhibition. Remarkably, 1,2-shift of the alkyl chain from C1 to O2 was found to maintain high inhibitory potency toward GCase as well as chaperone activity at sub-inhibitory concentration (10 nM). Removal of the stereogenic center at the pseudo-anomeric position led to shorter and more practical synthetic sequences. 2-O-Alkyl iminoxylitol derivatives constitute a new promising class of leads for the treatment of Gaucher disease by means of pharmacological chaperone therapy.