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 inhib...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2006-08, Vol.16 (15), p.3981-3984
Hauptverfasser: Smith, Garrick, Mikkelsen, Gitte, Eskildsen, Jørgen, Bundgaard, Christoffer
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container_end_page 3984
container_issue 15
container_start_page 3981
container_title Bioorganic & medicinal chemistry letters
container_volume 16
creator Smith, Garrick
Mikkelsen, Gitte
Eskildsen, Jørgen
Bundgaard, Christoffer
description 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.
doi_str_mv 10.1016/j.bmcl.2006.05.017
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subjects Amino acids
Amino Acids - chemical synthesis
Amino Acids - chemistry
Amino Acids - pharmacokinetics
Amino Acids - pharmacology
Biological and medical sciences
Blood-Brain Barrier
Caco-2 Cells
Glutamatergic system (aspartate and other excitatory aminoacids)
Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors
Glycine transporter-1
GlyT-1 inhibitor
Humans
Medical sciences
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Psycholeptics: tranquillizer, neuroleptic
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Schizophrenia
Structure-Activity Relationship
title The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors
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