Abstract
The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
MeSH terms
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Animals
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Brain / metabolism
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CHO Cells
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Cricetinae
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Cricetulus
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Glycine Plasma Membrane Transport Proteins / antagonists & inhibitors*
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Humans
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Macaca fascicularis
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Male
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Mice
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Microdialysis
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Motor Activity / drug effects
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Patch-Clamp Techniques
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Psychotropic Drugs / chemical synthesis*
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Psychotropic Drugs / pharmacokinetics
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Psychotropic Drugs / pharmacology
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Rats
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Rats, Sprague-Dawley
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Schizophrenia / drug therapy*
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Stereoisomerism
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / pharmacokinetics
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Sulfones / pharmacology
Substances
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(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Glycine Plasma Membrane Transport Proteins
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KCNH2 protein, human
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Piperazines
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Psychotropic Drugs
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SLC6A9 protein, human
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Sulfones