N-Butyl-l-deoxynojirimycin (l-NBDNJ): Synthesis of an Allosteric Enhancer of α-Glucosidase Activity for the Treatment of Pompe Disease

J Med Chem. 2017 Dec 14;60(23):9462-9469. doi: 10.1021/acs.jmedchem.7b00646. Epub 2017 Nov 22.

Abstract

The highly stereocontrolled de novo synthesis of l-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. l-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when coincubated with the recombinant human α-glucosidase. In addition, differently from its d-enantiomer, l-NBDNJ does not act as a glycosidase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / chemical synthesis
  • 1-Deoxynojirimycin / chemistry
  • 1-Deoxynojirimycin / pharmacology
  • Allosteric Regulation / drug effects
  • Cell Line
  • Enzyme Activation / drug effects*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Glycogen Storage Disease Type II / drug therapy*
  • Glycogen Storage Disease Type II / enzymology
  • Glycogen Storage Disease Type II / metabolism
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / enzymology
  • Lysosomes / metabolism
  • Models, Molecular
  • Stereoisomerism
  • alpha-Glucosidases / metabolism*

Substances

  • Enzyme Inhibitors
  • 1-Deoxynojirimycin
  • miglustat
  • alpha-Glucosidases