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).
Wu
Dongpei
D
Department of Medicinal Chemistry, Neurocrine Biosciences Inc. 12790 El Camino Real, San Diego, CA 92130, USA.
Pontillo
Joseph
J
Ching
Brett
B
Hudson
Sarah
S
Gao
Yinghong
Y
Fleck
Beth A
BA
Gogas
Kathleen
K
Wade
Warren S
WS
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