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

• Published in: Bioorganic & medicinal chemistry letters 2010-06, Vol.20 (12), p.3788-3792
• Main Authors: Fray, M. Jonathan, Fish, Paul V., Allan, Gillian A., Bish, Gerwyn, Clarke, Nick, Eccles, Rachel, Harrison, Anthony C., Net, Jean-Loic Le, Phillips, Stephen C., Regan, Nicola, Sobry, Cecile, Stobie, Alan, Wakenhut, Florian, Westbrook, Dominique, Westbrook, Simon L., Whitlock, Gavin A.
• Format: Article
• Language: English
• Subjects: 4-Piperazines; Adrenergic Uptake Inhibitors - chemistry; Adrenergic Uptake Inhibitors - metabolism; Adrenergic Uptake Inhibitors - pharmacokinetics; Animals; Biological and medical sciences; CYP2D6 metabolism; Dogs; Humans; Ion channel activity; Medical sciences; Metabolic stability; Norepinephrine; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Serotonin and noradrenaline reuptake inhibitor (SNRI); Serotonin Uptake Inhibitors - chemistry; Serotonin Uptake Inhibitors - metabolism; Serotonin Uptake Inhibitors - pharmacokinetics; Stress urinary incontinence; Structure-Activity Relationship; Urinary Incontinence, Stress - drug therapy; Urinary system
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.04.052

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI). Piperazine (−)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to previous examples. 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; R1) 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.