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

Wei Chieh Cheng, Chen Yi Weng, Wen Yi Yun, Shang Yu Chang, Yu Chun Lin, Fuu Jen Tsai, Fu-Yung Huang, Yun Ru Chen

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23 Citations (Scopus)

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 71 nM. 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.

Original languageEnglish
Pages (from-to)5021-5028
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number17
DOIs
Publication statusPublished - 2013 Sep 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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