title: 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.
authors.affiliation: Discovery Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Sandwich, Kent, UK.
authors.forename: M Jonathan
authors.initials: MJ
authors.lastname: Fray
authors.forename: Paul V
authors.initials: PV
authors.lastname: Fish
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Allan
authors.forename: Gerwyn
authors.initials: G
authors.lastname: Bish
authors.forename: Nick
authors.initials: N
authors.lastname: Clarke
authors.forename: Rachel
authors.initials: R
authors.lastname: Eccles
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Harrison
authors.forename: Jean-Loic
authors.initials: JL
authors.lastname: Le Net
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Phillips
authors.forename: Nicola
authors.initials: N
authors.lastname: Regan
authors.forename: Cecile
authors.initials: C
authors.lastname: Sobry
authors.forename: Alan
authors.initials: A
authors.lastname: Stobie
authors.forename: Florian
authors.initials: F
authors.lastname: Wakenhut
authors.forename: Dominique
authors.initials: D
authors.lastname: Westbrook
authors.forename: Simon L
authors.initials: SL
authors.lastname: Westbrook
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Whitlock
mesh_terms: 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*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D009638:Norepinephrine; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors