Structure–activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability

The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC50s < 10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC50s > 1 μM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.

Graphical abstractA series of chiral ring-constrained norepinephrine reuptake inhibitors equivalent to atomoxetine in potency, selectivity, and inhibition of CYP2D6 but more stable to oxidative metabolism.Figure optionsDownload full-size imageDownload as PowerPoint slide