Abstract
The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Adrenergic Uptake Inhibitors / chemical synthesis
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Adrenergic Uptake Inhibitors / chemistry*
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Adrenergic Uptake Inhibitors / pharmacokinetics
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Anilides / chemical synthesis
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Anilides / chemistry*
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Anilides / pharmacology
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Animals
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Benzamides / chemical synthesis
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Benzamides / chemistry*
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Benzamides / pharmacokinetics
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Cell Line
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Central Nervous System / metabolism*
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Dogs
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Dopamine Uptake Inhibitors / chemical synthesis
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Dopamine Uptake Inhibitors / chemistry
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Dopamine Uptake Inhibitors / pharmacokinetics
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Humans
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Norepinephrine / metabolism
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Pyrrolidines / chemical synthesis
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacology
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Rats
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Selective Serotonin Reuptake Inhibitors / chemical synthesis
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Selective Serotonin Reuptake Inhibitors / chemistry*
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Selective Serotonin Reuptake Inhibitors / pharmacokinetics
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Structure-Activity Relationship
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Adrenergic Uptake Inhibitors
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Anilides
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Benzamides
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Dopamine Uptake Inhibitors
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PF 184,298
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Pyrrolidines
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Serotonin Uptake Inhibitors
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Norepinephrine