Abstract
A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Crystallography, X-Ray
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Disease Models, Animal
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Humans
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / metabolism
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Neurotransmitter Uptake Inhibitors / pharmacology*
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Norepinephrine / antagonists & inhibitors
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Norepinephrine / chemistry
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Norepinephrine / metabolism
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Pain / drug therapy
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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 / pharmacology*
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Structure-Activity Relationship
Substances
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Nerve Tissue Proteins
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Neurotransmitter Uptake Inhibitors
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Pyrrolidines
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Serotonin Uptake Inhibitors
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Norepinephrine