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

  • J Med Chem. 2010 Jun 24;53(12):4603-14. doi: 10.1021/jm100210p.
Emmanuel Pinard  1 ,  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
Affiliations
  • 1. F. Hoffmann-La Roche Ltd., Pharmaceutical Division, CH-4070 Basel, Switzerland. [email protected]
PMID: 20491477 DOI: 10.1021/jm100210p
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.

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