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Bioorg Med Chem. 2018 Nov 1;26(20):5462-5469. doi: 10.1016/j.bmc.2018.09.023. Epub 2018 Sep 21.

4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to β-galactosidase mutations: Improved synthesis and biological investigations.

Author information

1
Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France.
2
Haute Ecole d'Ingénierie et d'Architecture Fribourg, Bd de Pérolles 80, 1705 Fribourg, Switzerland.
3
SIB (Swiss Institute of Bioinformatics), Quartier Sorge, 1015 Lausanne, Switzerland.
4
Dorphan, EPFL Innovation Park, 1015 Lausanne, Switzerland.
5
Greenwood Genetic Center, 106 Gregor Mendel Circle, Greenwood, SC 29646, USA.
6
Université d'Orléans & CNRS, Institut de Chimie Organique et Analytique (ICOA), UMR 7311, Rue de Chartres, 45067 Orléans, France. Electronic address: olivier.martin@univ-orleans.fr.
7
Dorphan, EPFL Innovation Park, 1015 Lausanne, Switzerland. Electronic address: demotz@dorphan.com.

Abstract

(5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated β-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring β-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring β-galactosidase mutations sensitive to pharmacological chaperoning.

PMID:
30270003
DOI:
10.1016/j.bmc.2018.09.023

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