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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Fray MJ,Fish PV,Allan GA,Bish G,Clarke N,Eccles R,Harrison AC,Le Net JL,Phillips SC,Regan N,Sobry C,Stobie A,Wakenhut F,Westbrook D,Westbrook SL,Whitlock GA

doi

10.1016/j.bmcl.2010.04.052

subject

Has Abstract

pub_date

2010-06-15 00:00:00

pages

3788-92

issue

12

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)00522-6

journal_volume

20

pub_type

杂志文章

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