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Amitifadine Synthesis Essay

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Fabrizio Micheli*†, Paolo Cavanni†, Roberto Arban†, Roberto Benedetti†, Barbara Bertani†, Michela Bettati†, Letizia Bettelini†, Giorgio Bonanomi†, Simone Braggio†, Anna Checchia†, Silvia Davalli‡, Romano Di Fabio†, Elettra Fazzolari†, Stefano Fontana†, Carla Marchioro‡, Doug Minick‡§, Michele Negri†, Beatrice Oliosi‡, Kevin D. Read∥, Ilaria Sartori†, Giovanna Tedesco‡, Luca Tarsi†, Silvia Terreni†, Filippo Visentini‡, Alessandro Zocchi† and Laura Zonzini†

Neurosciences Centre of Excellence for Drug Discovery

Molecular Discovery Research

GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy

§ Molecular Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina

Biological Chemistry and Drug Discovery, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, U.K.

J. Med. Chem., 2010, 53 (6), pp 2534–2551

DOI: 10.1021/jm901818u

Publication Date (Web): February 19, 2010

Copyright © 2010 American Chemical Society

*To whom correspondence should be addressed. Phone: +39-045-8218515. Fax: +39-045-8118196. E-mail:


The discovery of new highly potent and selective triple reuptake inhibitors is reported. The new classes of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes are described together with detailed SAR. 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.

An example of TRUI minimal pharmacophore construction. This material is available free of charge via the Internet at

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