The discovery and structure-activity relationships of indole-based inhibitors of glutamate carboxypeptidase II

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7222-5. doi: 10.1016/j.bmcl.2010.10.109. Epub 2010 Oct 26.

Abstract

A series of N-substituted 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acids were synthesized as inhibitors of glutamate carboxypeptidase II (GCPII). Those containing carboxybenzyl or carboxyphenyl groups at the N-position exhibited potent inhibitory activity against GCPII. These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCPII active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids
  • Drug Evaluation, Preclinical
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / metabolism
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Carboxylic Acids
  • Indoles
  • Protease Inhibitors
  • indole-2-carboxylic acid
  • Glutamate Carboxypeptidase II