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  • Title: 4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to β-galactosidase mutations: Improved synthesis and biological investigations.
    Author: Front S, Almeida S, Zoete V, Charollais-Thoenig J, Gallienne E, Marmy C, Pilloud V, Marti R, Wood T, Martin OR, Demotz S.
    Journal: Bioorg Med Chem; 2018 Nov 01; 26(20):5462-5469. PubMed ID: 30270003.
    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.
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