Synthesis and structure–activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with improved pharmaceutical characteristics

The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC50s <10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC50s > 1 μM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.

Graphical abstractNorepinephrine reuptake inhibitors with improved physicochemical properties are described. Typical compound are potent (IC50s < 10 nM), selective, weak CYP2D6 inhibitors (IC50s > 1 μM) and resistant to oxidation by human liver microsomes, with a favorable polarity profile.Figure optionsDownload full-size imageDownload as PowerPoint slide