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

研究成果: Article同行評審

24 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)5021-5028
頁數8
期刊Bioorganic and Medicinal Chemistry
21
發行號17
DOIs
出版狀態Published - 2013 九月 1

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子醫學
  • 分子生物學
  • 藥學科學
  • 藥物發現
  • 臨床生物化學
  • 有機化學

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