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

Synthesis and studies on the mGluR agonist activity of FAP4 stereoisomers.

Author information

1
NormandieUniv., COBRA, UMR 6014 & FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France.
2
Institut de Génomique Fonctionnelle, CNRS UMR5203, Université de Montpellier, F-34094 Montpellier, France; INSERM U1191, F-34094 Montpellier, France.
3
NormandieUniv., COBRA, UMR 6014 & FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France. Electronic address: philippe.jubault@insa-rouen.fr.

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

PMID:
25958247
DOI:
10.1016/j.bmcl.2015.04.043
[Indexed for MEDLINE]

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