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

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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

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

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3788-92. doi: 10.1016/j.bmcl.2010.04.052. Epub 2010 Apr 18.

PubMed ID

20471260 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Duloxetine	Sodium-dependent dopamine transporter	Ki (nM)	435	N/A	N/A	Details
Duloxetine	Sodium-dependent noradrenaline transporter	Ki (nM)	45	N/A	N/A	Details
Duloxetine	Sodium-dependent serotonin transporter	Ki (nM)	5	N/A	N/A	Details