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

被引：117

作者：

Pinard, Emmanuel ^{[1
]}

Alanine, Alexander ^{[1
]}

Alberati, Daniela ^{[1
]}

Bender, Markus ^{[1
]}

Borroni, Edilio ^{[1
]}

Bourdeaux, Patrick ^{[1
]}

Brom, Virginie ^{[1
]}

Burner, Serge ^{[1
]}

Fischer, Holger ^{[1
]}

Hainzl, Dominik ^{[1
]}

Halm, Remy ^{[1
]}

Hauser, Nicole ^{[1
]}

Jolidon, Synese ^{[1
]}

Lengyel, Judith ^{[1
]}

Marty, Hans-Peter ^{[1
]}

Meyer, Thierry ^{[1
]}

Moreau, Jean-Luc ^{[1
]}

Mory, Roland ^{[1
]}

Narquizian, Robert ^{[1
]}

Nettekoven, Mathias ^{[1
]}

Norcross, Roger D. ^{[1
]}

Puellmann, Bernd ^{[1
]}

Schmid, Philipp ^{[1
]}

Schmitt, Sebastien ^{[1
]}

Stalder, Henri ^{[1
]}

Wermuth, Roger ^{[1
]}

Wettstein, Joseph G. ^{[1
]}

Zimmerli, Daniel ^{[1
]}

机构：

[1] F Hoffmann La Roche & Co Ltd, Div Pharmaceut, CH-4070 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 12期

关键词：

GLYCINE TRANSPORTER TYPE-1; D-ASPARTATE RECEPTORS; SUBSTITUTED SPIROPIPERIDINES; POTENT; DESIGN; SITE; SAR;

D O I：

10.1021/jm100210p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4603 / 4614

页数：12

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