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  • Title: Rapid modifications of N-substitution in iminosugars: development of new β-glucocerebrosidase inhibitors and pharmacological chaperones for Gaucher disease.
    Author: Cheng WC, Weng CY, Yun WY, Chang SY, Lin YC, Tsai FJ, Huang FY, Chen YR.
    Journal: Bioorg Med Chem; 2013 Sep 01; 21(17):5021-8. PubMed ID: 23880081.
    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.
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