A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors

Angew Chem Int Ed Engl. 2015 Dec 14;54(51):15429-33. doi: 10.1002/anie.201507985. Epub 2015 Nov 6.

Abstract

Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.

Keywords: enzymes; glycosides; heterocycles; hydrolases; inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Cyclitols / chemistry
  • Cyclitols / pharmacokinetics*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Stereoisomerism
  • beta-N-Acetylhexosaminidases / antagonists & inhibitors*

Substances

  • Cyclitols
  • Enzyme Inhibitors
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases