Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI).
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).
Department of Medicinal Chemistry, Neurocrine Biosciences Inc. 12790 El Camino Real, San Diego, CA 92130, USA.
Dongpei
D
Wu
Joseph
J
Pontillo
Brett
B
Ching
Sarah
S
Hudson
Yinghong
Y
Gao
Beth A
BA
Fleck
Kathleen
K
Gogas
Warren S
WS
Wade
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D000588:Amines / Q000737:chemistry; D000069445:Atomoxetine Hydrochloride; D001665:Binding Sites; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003891:Desipramine / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D011437:Propylamines / Q000737:chemistry; D013329:Structure-Activity Relationship
D018759:Adrenergic Uptake Inhibitors; D000588:Amines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; D003891:Desipramine