Rapid preparation of (3R,4S,5R) polyhydroxylated pyrrolidine-based libraries to discover a pharmacological chaperone for treatment of Fabry disease

Eur J Med Chem. 2017 Jan 27;126:1-6. doi: 10.1016/j.ejmech.2016.10.004. Epub 2016 Oct 5.


The rapid discovery of a pharmacological chaperone toward human α-Gal A for the treatment of Fabry disease is described. Two polyhydroxylated pyrrolidines with the (3R,4S,5R) configuration pattern underwent rapid substituent diversity by conjugating the primary aminomethyl moiety of each with a variety of carboxylic acids to generate two libraries (2 × 60 members). Our bioevaluation results showed one member with the (2R,3R,4S,5R) configuration pattern and bearing a 5-cyclohexylpentanoyl group as a substituent moiety possessed sufficient chaperoning capability to rescue α-Gal A activity in the lymphocyte of the N215S Fabry patient-derived cell line and other α-Gal A mutants in COS7 cells.

Keywords: Azasugar; Combinatorial chemistry; Fabry disease; Lysosomal α-galactosidase; Pharmacological chaperone; Polyhydroxylated pyrrolidine.

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Drug Design*
  • Drug Stability
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Fabry Disease / drug therapy*
  • Humans
  • Hydroxylation
  • Kinetics
  • Mutation
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / therapeutic use
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use
  • Stereoisomerism
  • Temperature
  • alpha-Galactosidase / antagonists & inhibitors
  • alpha-Galactosidase / genetics


  • Enzyme Inhibitors
  • Pyrrolidines
  • Small Molecule Libraries
  • alpha-Galactosidase