The synthesis and SAR of 2-arylsulfanyl-phenyl piperazinyl acetic acids as glyT-1 inhibitors

Bioorganic & Medicinal Chemistry Letters
Garrick SmithGuillaume Brandt

Abstract

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.

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Citations

Jun 7, 2006·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Yasushi Shigeri, Keiko Shimamoto
Jan 22, 2011·The Open Medicinal Chemistry Journal·Kenji Hashimoto
Apr 24, 2012·British Journal of Pharmacology·Stefan Bröer, Ulrik Gether
Apr 28, 2009·Pharmacology & Therapeutics·Toshihiro DohiNorimitsu Morioka
Jun 16, 2005·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Ronan DepoortèreBernard Scatton
Jul 15, 2011·Pharmacological Reviews·Anders S KristensenUlrik Gether
Aug 15, 2017·Angewandte Chemie·Cecilia BottecchiaTimothy Noël
Apr 18, 2019·The Journal of Organic Chemistry·Yi-Chen ShiehChin-Fa Lee

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