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.
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.
Pinard
Emmanuel
E
F. Hoffmann-La Roche Ltd., Pharmaceutical Division, CH-4070 Basel, Switzerland. emmanuel.pinard@roche.com
Alanine
Alexander
A
Alberati
Daniela
D
Bender
Markus
M
Borroni
Edilio
E
Bourdeaux
Patrick
P
Brom
Virginie
V
Burner
Serge
S
Fischer
Holger
H
Hainzl
Dominik
D
Halm
Remy
R
Hauser
Nicole
N
Jolidon
Synese
S
Lengyel
Judith
J
Marty
Hans-Peter
HP
Meyer
Thierry
T
Moreau
Jean-Luc
JL
Mory
Roland
R
Narquizian
Robert
R
Nettekoven
Mathias
M
Norcross
Roger D
RD
Puellmann
Bernd
B
Schmid
Philipp
P
Schmitt
Sebastien
S
Stalder
Henri
H
Wermuth
Roger
R
Wettstein
Joseph G
JG
Zimmerli
Daniel
D
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
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