The synthesis and SAR of 2-arylsulfanyl-phenyl piperazinyl acetic acids as glyT-1 inhibitors.
Elevation of glycine levels and activation of the NMDA receptor by inhibition of the glycine transporter 1 (GlyT-1) is a potential strategy for the treatment of schizophrenia. A novel series of GlyT-1 inhibitors have been identified containing the 2-arylsulfanyl-phenylpiperazine motif. The most prominent member of this series, (R)-4-[5-chloro-2-(4-methoxy-phenylsulfanyl)-phenyl]-2-methyl-piperazin-1-yl-acetic acid (31) is a potent glycine transporter-1 inhibitor (IC(50)=150 nM), which elevated glycine levels in rat ventral hippocampus as measured by microdialysis in vivo at doses of 1.2-4.6 mg/kg s.c.
Smith
Garrick
G
Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK 2500 Valby, Denmark. gsm@lundbeck.com
Ruhland
Thomas
T
Mikkelsen
Gitte
G
Andersen
Kim
K
Christoffersen
Claus Tornby
CT
Alifrangis
Lene Hjorth
LH
Mørk
Arne
A
Wren
Stephen P
SP
Harris
Neil
N
Wyman
Barry M
BM
Brandt
Guillaume
G
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D026921:Amino Acid Transport Systems, Neutral / Q000037:antagonists & inhibitors*; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000085:Acetates; D026921:Amino Acid Transport Systems, Neutral; D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C493268:SLC6A9 protein, human; C493266:Slc6a9 protein, rat; D005998:Glycine