5-Fluoro derivatives of 4-epi-isofagomine as D-galactosidase inhibitors and potential pharmacological chaperones for GM1-gangliosidosis as well as Fabry's disease

Carbohydr Res. 2016 Feb:420:6-12. doi: 10.1016/j.carres.2015.10.009. Epub 2015 Dec 8.

Abstract

Electrophilic fluorination of an exocyclic methoxymethylene enol ether derived from N-tert-butyloxycarbonyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-D-erythro-pent-2-ulose (11) provided the 5-fluoro derivative of the powerful β-galactosidase inhibitor 4-epi-isofagomine (8). This structural alteration, in combination with N-alkylation, led to considerably improved α-galactosidase selectivity. New compounds may serve as leads en route to new pharmacological chaperones for Fabry's disease.

Keywords: Fabry's disease; Fluorosugar; G(M1)-gangliosidosis; Galactosidase inhibitor; Iminoalditol; Pharmacological chaperone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fabry Disease / drug therapy
  • Fabry Disease / enzymology
  • Galactosidases / antagonists & inhibitors*
  • Gangliosidosis, GM1 / drug therapy
  • Gangliosidosis, GM1 / enzymology
  • Halogenation
  • Humans
  • Imino Pyranoses / chemical synthesis*
  • Imino Pyranoses / chemistry
  • Imino Pyranoses / pharmacology
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Imino Pyranoses
  • isofagomine
  • Galactosidases