1-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(Aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Triple Reuptake Inhibitors

被引：46

作者：

Micheli, Fabrizio ^{[1
]}

Cavanni, Paolo ^{[1
]}

Arban, Roberto ^{[1
]}

Benedetti, Roberto ^{[1
]}

Bertani, Barbara ^{[1
]}

Bettati, Michela ^{[1
]}

Bettelini, Letizia ^{[1
]}

Bonanomi, Giorgio ^{[1
]}

Braggio, Simone ^{[1
]}

Checchia, Anna ^{[1
]}

Davalli, Silvia ^{[2
]}

Di Fabio, Romano ^{[1
]}

Fazzolari, Elettra ^{[1
]}

Fontana, Stefano ^{[1
]}

Marchioro, Carla ^{[2
]}

Minick, Doug ^{[2
,3
]}

Negri, Michele ^{[1
]}

Oliosi, Beatrice ^{[2
]}

Read, Kevin D. ^{[4
]}

Sartori, Ilaria ^{[1
]}

Tedesco, Giovanna ^{[2
]}

Tarsi, Luca ^{[1
]}

Terreni, Silvia ^{[1
]}

Visentini, Filippo ^{[2
]}

Zocchi, Alessandro ^{[1
]}

Zonzini, Laura ^{[1
]}

机构：

[1] GlaxoSmithKline Med Res Ctr, Neurosci Ctr Excellence Drug Discovery, I-37135 Verona, Italy

[2] GlaxoSmithKline Med Res Ctr, Mol Discovery Res, I-37135 Verona, Italy

[3] GlaxoSmithKline Inc, Mol Discovery Res, Res Triangle Pk, NC USA

[4] Univ Dundee, Sir James Black Ctr, Coll Life Sci, Dundee DD1 5EH, Scotland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 06期

关键词：

DEPRESSION; MONOAMINES; DOPAMINE;

D O I：

10.1021/jm901818u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(ary1)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SA R. Appropriate decoration of the scaffolds was achieved with the help of a triple reuptake inhibitor pharmacophore model detailed here. Selected derivatives showed good oral bioavailability ( > 30%) and brain penetration (B/B > 4) in rats associated with high in vitro potency and selectivity at SERT, NET, and DAT. Among these compounds, microdialysis and in vivo experiments confirm that derivative 15 has an appropriate developability profile to be considered for further progression.

引用

页码：2534 / 2551

页数：18

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