Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: improving metabolic stability and reducing ion channel activity.
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.
Fray
M Jonathan
MJ
Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent, UK.
Fish
Paul V
PV
Allan
Gillian A
GA
Bish
Gerwyn
G
Clarke
Nick
N
Eccles
Rachel
R
Harrison
Anthony C
AC
Le Net
Jean-Loic
JL
Phillips
Stephen C
SC
Regan
Nicola
N
Sobry
Cecile
C
Stobie
Alan
A
Wakenhut
Florian
F
Westbrook
Dominique
D
Westbrook
Simon L
SL
Whitlock
Gavin A
GA
D018759:Adrenergic Uptake Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D004285:Dogs; D006801:Humans; D009638:Norepinephrine; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014550:Urinary Incontinence, Stress / Q000188:drug therapy*
D018759:Adrenergic Uptake Inhibitors; D009638:Norepinephrine; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors