The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors

Elevation of glycine levels by inhibition of the glycine transporter-1 (GlyT-1) and activation of the NMDA receptor is a potential strategy for the treatment of schizophrenia. A novel series of 2-arylsulfanylphenyl-1-oxyalkyl amino acids have been identified. The most prominent member of this series S-1-{2-[3-(3-fluoro-phenylsulfanyl)biphenyl-4-yloxy]ethyl}pyrrolidine-2-carboxylic acid (38) is a potent GlyT-1 inhibitor (IC50 = 59 nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.

Graphical abstractA novel series of GlyT-1 inhibitors is described. The most potent compound, 38, has a GlyT-1b IC50 = 59 nM. In vitro and in vivo assessment of CNS penetration showed that lead compounds had poor CNS exposure most likely due to active efflux by PgP transporters.Figure optionsDownload full-size imageDownload as PowerPoint slide