title: 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.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceutical Division, CH-4070 Basel, Switzerland. emmanuel.pinard@roche.com
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Pinard
authors.forename: Alexander
authors.initials: A
authors.lastname: Alanine
authors.forename: Daniela
authors.initials: D
authors.lastname: Alberati
authors.forename: Markus
authors.initials: M
authors.lastname: Bender
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: Patrick
authors.initials: P
authors.lastname: Bourdeaux
authors.forename: Virginie
authors.initials: V
authors.lastname: Brom
authors.forename: Serge
authors.initials: S
authors.lastname: Burner
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Dominik
authors.initials: D
authors.lastname: Hainzl
authors.forename: Remy
authors.initials: R
authors.lastname: Halm
authors.forename: Nicole
authors.initials: N
authors.lastname: Hauser
authors.forename: Synese
authors.initials: S
authors.lastname: Jolidon
authors.forename: Judith
authors.initials: J
authors.lastname: Lengyel
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Marty
authors.forename: Thierry
authors.initials: T
authors.lastname: Meyer
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Moreau
authors.forename: Roland
authors.initials: R
authors.lastname: Mory
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
authors.forename: Mathias
authors.initials: M
authors.lastname: Nettekoven
authors.forename: Roger D
authors.initials: RD
authors.lastname: Norcross
authors.forename: Bernd
authors.initials: B
authors.lastname: Puellmann
authors.forename: Philipp
authors.initials: P
authors.lastname: Schmid
authors.forename: Sebastien
authors.initials: S
authors.lastname: Schmitt
authors.forename: Henri
authors.initials: H
authors.lastname: Stalder
authors.forename: Roger
authors.initials: R
authors.lastname: Wermuth
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.forename: Daniel
authors.initials: D
authors.lastname: Zimmerli
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C550631:(4-(3-fluoro-5-trifluoromethylpyridin-2-yl)piperazin-1-yl)(5-methanesulfonyl-2-(2,2,2-trifluoro-1-methylethoxy)phenyl)methanone; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D050487:Glycine Plasma Membrane Transport Proteins; C000606913:KCNH2 protein, human; D010879:Piperazines; D011619:Psychotropic Drugs; C493268:SLC6A9 protein, human; D013450:Sulfones