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.
Smith
Garrick
G
Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK 2500 Valby, Denmark. gsm@lundbeck.com
Mikkelsen
Gitte
G
Eskildsen
Jørgen
J
Bundgaard
Christoffer
C
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D018938:Caco-2 Cells; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D013329:Structure-Activity Relationship
D000596:Amino Acids; D050487:Glycine Plasma Membrane Transport Proteins