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.
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.
Micheli
Fabrizio
F
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicine Research Centre, Via Fleming 4, 37135 Verona, Italy. Fabrizio.E.Micheli@gsk.com
Cavanni
Paolo
P
Arban
Roberto
R
Benedetti
Roberto
R
Bertani
Barbara
B
Bettati
Michela
M
Bettelini
Letizia
L
Bonanomi
Giorgio
G
Braggio
Simone
S
Checchia
Anna
A
Davalli
Silvia
S
Di Fabio
Romano
R
Fazzolari
Elettra
E
Fontana
Stefano
S
Marchioro
Carla
C
Minick
Doug
D
Negri
Michele
M
Oliosi
Beatrice
B
Read
Kevin D
KD
Sartori
Ilaria
I
Tedesco
Giovanna
G
Tarsi
Luca
L
Terreni
Silvia
S
Visentini
Filippo
F
Zocchi
Alessandro
A
Zonzini
Laura
L
D000818:Animals; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D015306:Biogenic Monoamines / Q000378:metabolism; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D017551:Microdialysis; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship
D053961:Azabicyclo Compounds; D015306:Biogenic Monoamines; D065607:Cytochrome P-450 Enzyme Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D003577:Cytochrome P-450 Enzyme System