Second-Generation Iminoxylitol-Based Pharmacological Chaperones for the Treatment of Gaucher Disease

作者：Oulaidi Farah^*; Front Deschamps Sophie; Gallienne Estelle; Lesellier Eric; Ikeda Kyoko; Asano Naoki; Compain Philippe; Martin Olivier R

来源：ChemMedChem, 2011, 6(2): 353-361.

DOI：10.1002/cmdc.201000469

• drug design
• gaucher disease
• glycosidase inhibitors
• iminosugars
• pharmacological chaperone

A series of O-alkyl iminoxylitol derivatives was synthesized and evaluated as beta-glucocerebrosidase (GCase) inhibitors. This structure-activity study shows a dramatic influence of the position of the alkyl chain (alpha-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.

• 出版日期2011-2-7