Α-amino-β-fluorocyclopropanecarboxylic acids as a new tool for drug development: synthesis of glutamic acid analogs and agonist activity towards metabotropic glutamate receptor 4

Bioorg Med Chem. 2012 Aug 1;20(15):4716-26. doi: 10.1016/j.bmc.2012.06.006. Epub 2012 Jun 15.

Abstract

Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Cells, Cultured
  • Cyclopropanes / chemical synthesis
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Glutamic Acid / chemical synthesis
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Receptors, Metabotropic Glutamate / agonists*
  • Recombinant Proteins / agonists
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Carboxylic Acids
  • Cyclopropanes
  • Receptors, Metabotropic Glutamate
  • Recombinant Proteins
  • alpha-amino-beta-fluorocyclopropanecarboxylic acid
  • Glutamic Acid
  • metabotropic glutamate receptor 4