Human Acid β-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease

Chembiochem. 2015 Sep 21;16(14):2054-64. doi: 10.1002/cbic.201500292.

Abstract

A collection of carbohydrate-derived iminosugars belonging to three structurally diversified sub-classes (polyhydroxylated pyrrolidines, piperidines, and pyrrolizidines) was evaluated for inhibition of human acid β-glucosidase (glucocerebrosidase, GCase), the deficient enzyme in Gaucher disease. The synthesis of several new pyrrolidine analogues substituted at the nitrogen or α-carbon atom with alkyl chains of different lengths suggested an interpretation of the inhibition data and led to the discovery of two new GCase inhibitors at sub-micromolar concentration. In the piperidine iminosugar series, two N-alkylated derivatives were found to rescue the residual GCase activity in N370S/RecNcil mutated human fibroblasts (among which one up to 1.5-fold). This study provides the starting point for the identification of new compounds in the treatment of Gaucher disease.

Keywords: GCase inhibition; Gaucher disease; iminosugars; natural products; synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Discovery
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Gaucher Disease / drug therapy
  • Gaucher Disease / enzymology*
  • Glucosylceramidase / antagonists & inhibitors*
  • Glucosylceramidase / metabolism
  • Humans
  • Imino Sugars / chemistry*
  • Imino Sugars / pharmacology*

Substances

  • Enzyme Inhibitors
  • Imino Sugars
  • Glucosylceramidase