Isosorbide-2-carbamate esters: potent and selective butyrylcholinesterase inhibitors

J Med Chem. 2008 Oct 23;51(20):6400-9. doi: 10.1021/jm800564y. Epub 2008 Sep 26.


In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase ( huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar potency with high selectivity for BuChE over acetylcholinesterase (AChE). The most potent and selective compound was isosorbide-2-benzyl carbamate-5-benzoate with an IC 50 of 4.3 nM for BuChE and >50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Butyrylcholinesterase / metabolism*
  • Carbamates / chemistry*
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Esters / chemical synthesis*
  • Esters / chemistry
  • Esters / pharmacology*
  • Humans
  • Isosorbide / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship


  • Carbamates
  • Cholinesterase Inhibitors
  • Esters
  • Butyrylcholinesterase
  • Isosorbide