Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI)

Dongpei Wu; Joseph Pontillo; Brett Ching; Sarah Hudson; Yinghong Gao; Beth A Fleck; Kathleen Gogas; Warren S Wade

doi:10.1016/j.bmcl.2008.05.057

Discovery of a potent, selective, and less flexible selective norepinephrine reuptake inhibitor (sNRI)

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4224-7. doi: 10.1016/j.bmcl.2008.05.057. Epub 2008 May 20.

Authors

Dongpei Wu¹, Joseph Pontillo, Brett Ching, Sarah Hudson, Yinghong Gao, Beth A Fleck, Kathleen Gogas, Warren S Wade

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences Inc. 12790 El Camino Real, San Diego, CA 92130, USA.

PMID: 18550369
DOI: 10.1016/j.bmcl.2008.05.057

Abstract

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).

MeSH terms

Adrenergic Uptake Inhibitors / chemical synthesis*
Adrenergic Uptake Inhibitors / pharmacology*
Amines / chemistry
Atomoxetine Hydrochloride
Binding Sites
Cell Line
Chemistry, Pharmaceutical / methods
Desipramine / chemistry
Drug Design
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
Norepinephrine Plasma Membrane Transport Proteins / chemical synthesis*
Norepinephrine Plasma Membrane Transport Proteins / pharmacology*
Propylamines / chemistry
Structure-Activity Relationship

Substances

Adrenergic Uptake Inhibitors
Amines
Norepinephrine Plasma Membrane Transport Proteins
Propylamines
Atomoxetine Hydrochloride
Desipramine