Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor

J Med Chem. 2010 Feb 11;53(3):1190-9. doi: 10.1021/jm9014845.

Abstract

Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anions / chemistry
  • Anions / metabolism*
  • Binding Sites
  • Butyrylcholinesterase / blood
  • Butyrylcholinesterase / chemistry*
  • Butyrylcholinesterase / genetics
  • Carbamates / chemistry*
  • Carbamates / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Intestines / drug effects
  • Intestines / enzymology
  • Isosorbide / analogs & derivatives*
  • Isosorbide / chemical synthesis
  • Isosorbide / chemistry*
  • Isosorbide / metabolism
  • Isosorbide / pharmacology
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Models, Molecular
  • Molecular Structure
  • Mutation / genetics
  • Salicylates / chemical synthesis
  • Salicylates / chemistry
  • Salicylates / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anions
  • Carbamates
  • Cholinesterase Inhibitors
  • Salicylates
  • isosorbide-2-benzyl carbamate-5-salicylate
  • Butyrylcholinesterase
  • Isosorbide