| Literature DB >> 20170186 |
Fabrizio Micheli1, 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, Laura Zonzini.
Abstract
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.Entities:
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Year: 2010 PMID： 20170186 DOI： 10.1021/jm901818u
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446