Synthesis and studies on the mGluR agonist activity of FAP4 stereoisomers

Bioorg Med Chem Lett. 2015 Jun 15;25(12):2523-6. doi: 10.1016/j.bmcl.2015.04.043. Epub 2015 Apr 22.

Abstract

The four stereoisomers of 1-amino-2-fluoro-2-(phosphonomethyl)cyclopropane-1-carboxylic acid (FAP4) were synthesized via diastereoselective Rh(II)-catalysed cyclopropanation of a phosphonylated fluoroalkene. Different isomers of FAP4 and the corresponding non-fluorinated analogs showed a similar pharmacological profile against the isoforms of metabotropic glutamate receptor (mGluR). Within the fluorinated series, (-)-(Z)-FAP4 and (-)-(E)-FAP4 demonstrated the highest agonist activity against mGlu4 (EC50 0.10 μM). Our results suggest that fluorocyclopropanes bearing an amino-acid function can be suitable for the development of potent conformationally restricted mGluR agonists.

Keywords: Amino-acids; Cyclopropane; Fluorine; Metabotropic glutamate receptor; Phosphonic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / metabolism
  • Cyclopropanes / chemistry
  • Glutamic Acid / chemistry
  • Glutamic Acid / metabolism
  • Protein Binding
  • Protein Isoforms / agonists
  • Protein Isoforms / metabolism
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism
  • Stereoisomerism

Substances

  • Carboxylic Acids
  • Cyclopropanes
  • Protein Isoforms
  • Receptors, Metabotropic Glutamate
  • Glutamic Acid
  • cyclopropane