Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3 oxopropyl)pentanedioic acid: A novel Selective inhibitor of human excitatory amino acid transporter subtype 2

Emmanuelle Sagot (1) , Anders A. Jensen (2) , Darryl S. Pickering (3) , Xiasui Pu (4) , Michelle Umberti (5) , Tine B. Stensbol (6) , Brigitte Nielsen (2) , Zeinab Assaf (1) , Bettina Aboab (1) , Jean Bolte (1) , Thierry Gefflaut (1) , Lennart Bunch (2)

1 SEESIB - Synthèse et étude de systèmes à intêret biologique
2 Department of Medicinal Chemistry
3 Department of Pharmacology and Pharmacotherapy [Copenhagen]
4 Biological Research - H. Lundbeck
5 H. Lundbeck - Biological Research
6 H. Lundbeck - Department of Neurobiology

In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of (S)-glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1−4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a−k (2d is exempt) with different functionalities in the 4R-position and characterized their pharmacological properties at the human EAAT1−3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far

Domaines: Chimie thérapeutique

Emmanuelle Sagot, Anders A. Jensen, Darryl S. Pickering, Xiasui Pu, Michelle Umberti, et al.. Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3 oxopropyl)pentanedioic acid: A novel Selective inhibitor of human excitatory amino acid transporter subtype 2. Journal of Medicinal Chemistry, 2008, 51, pp.4085-4092. ⟨hal-00323786⟩