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

• Published in: ChemMedChem Vol. 6; no. 2; pp. 353 - 361
• Main Authors: Oulaïdi, Farah, Front-Deschamps, Sophie, Gallienne, Estelle, Lesellier, Eric, Ikeda, Kyoko, Asano, Naoki, Compain, Philippe, Martin, Olivier R.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 07.02.2011; WILEY‐VCH Verlag; Wiley-VCH Verlag
• Subjects: Chemical Sciences; Chromatography, Liquid; drug design; gaucher disease; Gaucher Disease - drug therapy; glycosidase inhibitors; Humans; iminosugars; pharmacological chaperone; Stereoisomerism; Xylitol - chemistry; Xylitol - therapeutic use
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000469

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. Simplify without sacrificing potency: Shifting the alkyl chain from the pseudo‐anomeric position to O2 in iminoxylitol derivatives maintains high inhibitory potency toward glucosylceramidase as well as chaperone activity at sub‐inhibitory concentration (10 nM). This structural simplification leads to shorter and more practical synthetic sequences.