Design, synthesis and evaluation of N-[(3S)-pyrrolidin-3-yl]benzamides as selective noradrenaline reuptake inhibitors: CNS penetration in a more polar template

Derivatives of N-[(3S)-pyrrolidin-3-yl]benzamides are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Benzamide 11e was identified as a potent NRI with good selectivity over SRI and DRI, good in vitro metabolic stability, weak CYP inhibition and low affinity for ion channels. Evaluation in vivo, in rat microdialysis experiments, showed 11e increased noradrenaline levels by up to 350% confirming good CNS penetration. Benzamide 11e was differentiated from previous NRIs as it was significantly less lipophilic.