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

✍ Scribed by Farah Oulaïdi; Sophie Front-Deschamps; Dr. Estelle Gallienne; Dr. Eric Lesellier; Kyoko Ikeda; Dr. Naoki Asano; Prof. Philippe Compain; Prof. Olivier R. Martin

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 360 KB
• Volume: 6
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.201000469

✦ Synopsis

Abstract

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.