Selective GlyT1 inhibitors: discovery of [4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl][5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)phenyl]methanone (RG1678), a promising novel medicine to treat schizophrenia.

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.
Authors	Emmanuel Pinard, Alexander Alanine, Daniela Alberati, Markus Bender, Edilio Borroni, Patrick Bourdeaux, Virginie Brom, Serge Burner, Holger Fischer, Dominik Hainzl, Remy Halm, Nicole Hauser, Synese Jolidon, Judith Lengyel, Hans-Peter Marty, Thierry Meyer, Jean-Luc Moreau, Roland Mory, Robert Narquizian, Mathias Nettekoven, Roger D Norcross, Bernd Puellmann, Philipp Schmid, Sebastien Schmitt, Henri Stalder, Roger Wermuth, Joseph G Wettstein, Daniel Zimmerli
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 12 Pg. 4603-14 (Jun 24 2010) ISSN: 1520-4804 [Electronic] United States
PMID	20491477 (Publication Type: Journal Article)
Chemical References	(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Glycine Plasma Membrane Transport Proteins KCNH2 protein, human Piperazines Psychotropic Drugs SLC6A9 protein, human Sulfones
Topics	Animals Brain (metabolism) CHO Cells Cricetinae Cricetulus ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels (antagonists & inhibitors) Glycine Plasma Membrane Transport Proteins (antagonists & inhibitors) Humans Macaca fascicularis Male Mice Microdialysis Motor Activity (drug effects) Patch-Clamp Techniques Piperazines (chemical synthesis, pharmacokinetics, pharmacology) Psychotropic Drugs (chemical synthesis, pharmacokinetics, pharmacology) Rats Rats, Sprague-Dawley Schizophrenia (drug therapy) Stereoisomerism Structure-Activity Relationship Sulfones (chemical synthesis, pharmacokinetics, pharmacology)

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