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
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 J. Minick, Michele Negri, Beatrice Oliosi, Kevin D. Read, Ilaria Sartori · Journal of Medicinal Chemistry · 2010
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.