Synthesis and studies on the mGluR agonist activity of FAP4 stereoisomers

Pavel Ivashkin (1) , Gérald Lemonnier (1) , Amélie S. Tora (2) , Jean-Philippe Pin (2) , Cyril Goudet (2) , Philippe Jubault (1) , Xavier Pannecoucke (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 IGF - Institut de Génomique Fonctionnelle

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 microM). Our results suggest that fluorocyclopropanes bearing an amino-acid function can be suitable for the development of potent conformationally restricted mGluR agonists.

Domaines: Chimie organique; Chimie thérapeutique; Chimie analytique; Catalyse; Chemo-informatique; Chimie théorique et/ou physique

Pavel Ivashkin, Gérald Lemonnier, Amélie S. Tora, Jean-Philippe Pin, Cyril Goudet, et al.. Synthesis and studies on the mGluR agonist activity of FAP4 stereoisomers. Bioorganic and Medicinal Chemistry Letters, 2015, 25 (12), pp.2523-2526. ⟨10.1016/j.bmcl.2015.04.043⟩. ⟨hal-01180138⟩