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Bioorg Med Chem. 2013 Sep 1;21(17):5021-8. doi: 10.1016/j.bmc.2013.06.054. Epub 2013 Jul 2.

Rapid modifications of N-substitution in iminosugars: development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease.

Author information

1
Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan. wcheng@gate.sinica.edu.tw

Abstract

The rapid discovery of β-glucocerebrosidase (GCase) inhibitors and pharmacological chaperones for Gaucher disease is described. The N-aminobutyl DNJ-based iminosugar was synthesized and conjugating with a variety of carboxylic acids to generate a N-diversely substituted iminosugar-based library. Several members of this library were found to be nanomolar-range inhibitors of GCase; the inhibition constant Ki of the most potent was found to be 71nM. Although these new molecules showed reasonable chaperoning activity (1.5- to 1.9-fold) in the N370S fibroblast of Gaucher patient-derived cell line, this was accompanies by a concomitant decrease in the cellular α-glucosidase activity, which might limit their further therapeutic potential. Next, newly developed N-substituents were assembled with pyrrolidine-based scaffolds to generate new molecules for further evaluation. The new 2,5-dideoxy-2,5-imino-d-mannitol (DMDP)-based iminosugar 22 was found to exhibit a satisfactory chaperoning activity to enhance GCase activity by 2.2-fold in Gaucher N370S cell line, without impairment of cellular α-glucosidase activity.

KEYWORDS:

Chemical chaperone; GCase inhibitor; Gaucher disease; Glycosidases; Iminosugar

PMID:
23880081
DOI:
10.1016/j.bmc.2013.06.054
[Indexed for MEDLINE]

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