title: Second-generation iminoxylitol-based pharmacological chaperones for the treatment of Gaucher disease.
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.
authors.affiliation: ICOA, UMR 6005, Université d'Orléans et CNRS rue de Chartres, BP 6759, 45067 Orléans, France.
authors.forename: Farah
authors.initials: F
authors.lastname: Oulaïdi
authors.forename: Sophie
authors.initials: S
authors.lastname: Front-Deschamps
authors.forename: Estelle
authors.initials: E
authors.lastname: Gallienne
authors.forename: Eric
authors.initials: E
authors.lastname: Lesellier
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ikeda
authors.forename: Naoki
authors.initials: N
authors.lastname: Asano
authors.forename: Philippe
authors.initials: P
authors.lastname: Compain
authors.forename: Olivier R
authors.initials: OR
authors.lastname: Martin
mesh_terms: D002853:Chromatography, Liquid; D005776:Gaucher Disease / Q000188:drug therapy*; D006801:Humans; D013237:Stereoisomerism; D014993:Xylitol / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D014993:Xylitol