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 Minick; Michele Negri; Beatrice Oliosi; Kevin D. Read; Ilaria Sartori; Giovanna Tedesco; Luca Tarsi; Silvia Terreni; Filippo Visentini; Alessandro Zocchi; Laura Zonzini

doi:10.1021/jm901818u

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 Minick, Michele Negri, Beatrice Oliosi, Kevin D. Read, Ilaria SartoriGiovanna Tedesco, Luca Tarsi, Silvia Terreni, Filippo Visentini, Alessandro Zocchi, Laura Zonzini

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	2534-2551
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	6
DOIs	https://doi.org/10.1021/jm901818u
Publication status	Published - 25 Mar 2010

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Micheli, F., Cavanni, P., Arban, R., Benedetti, R., Bertani, B., Bettati, M., Bettelini, L., Bonanomi, G., Braggio, S., Checchia, A., Davalli, S., Di Fabio, R., Fazzolari, E., Fontana, S., Marchioro, C., Minick, D., Negri, M., Oliosi, B., Read, K. D., ... Zonzini, L. (2010). 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. Journal of Medicinal Chemistry, 53(6), 2534-2551. https://doi.org/10.1021/jm901818u

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title = "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",

abstract = "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.",

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

year = "2010",

month = mar,

day = "25",

doi = "10.1021/jm901818u",

language = "English",

volume = "53",

pages = "2534--2551",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "6",

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Micheli, F, Cavanni, P, Arban, R, Benedetti, R, Bertani, B, Bettati, M, Bettelini, L, Bonanomi, G, Braggio, S, Checchia, A, Davalli, S, Di Fabio, R, Fazzolari, E, Fontana, S, Marchioro, C, Minick, D, Negri, M, Oliosi, B, Read, KD, Sartori, I, Tedesco, G, Tarsi, L, Terreni, S, Visentini, F, Zocchi, A & Zonzini, L 2010, '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', Journal of Medicinal Chemistry, vol. 53, no. 6, pp. 2534-2551. https://doi.org/10.1021/jm901818u

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. / Micheli, Fabrizio; Cavanni, Paolo; Arban, Roberto et al.
In: Journal of Medicinal Chemistry, Vol. 53, No. 6, 25.03.2010, p. 2534-2551.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes and 6-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes

T2 - a new series of potent and selective triple reuptake inhibitors

AU - Micheli, Fabrizio

AU - Cavanni, Paolo

AU - Arban, Roberto

AU - Benedetti, Roberto

AU - Bertani, Barbara

AU - Bettati, Michela

AU - Bettelini, Letizia

AU - Bonanomi, Giorgio

AU - Braggio, Simone

AU - Checchia, Anna

AU - Davalli, Silvia

AU - Di Fabio, Romano

AU - Fazzolari, Elettra

AU - Fontana, Stefano

AU - Marchioro, Carla

AU - Minick, Doug

AU - Negri, Michele

AU - Oliosi, Beatrice

AU - Read, Kevin D.

AU - Sartori, Ilaria

AU - Tedesco, Giovanna

AU - Tarsi, Luca

AU - Terreni, Silvia

AU - Visentini, Filippo

AU - Zocchi, Alessandro

AU - Zonzini, Laura

PY - 2010/3/25

Y1 - 2010/3/25

N2 - 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.

AB - 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.

U2 - 10.1021/jm901818u

DO - 10.1021/jm901818u

M3 - Article

C2 - 20170186

SN - 0022-2623

VL - 53

SP - 2534

EP - 2551

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 6

ER -

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

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