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

A novel series of GlyT-1 inhibitors is described. The most potent compound, 38, has a GlyT-1 b IC 50 = 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. 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 (IC 50 = 59 nM). In vitro and in vivo assessment of CNS exposure indicates this compound is a likely substrate for active efflux transporters.