Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: Improving metabolic stability and reducing ion channel activity

Abstract New N -(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 ( 4 ) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4 , detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings ( 6 : R; R 1 ) combined with a preferred stereochemistry. From this set of compounds, piperazine (−)- 6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4 . Based on this profile, (−)- 6a was selected for further evaluation in a preclinical model of SUI.