Abstract
The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
MeSH terms
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Adrenergic Uptake Inhibitors / chemical synthesis*
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Adrenergic Uptake Inhibitors / chemistry
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Adrenergic Uptake Inhibitors / pharmacology*
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Atomoxetine Hydrochloride
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Chemistry, Pharmaceutical / methods*
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Cytochrome P-450 CYP2D6 / chemistry
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Drug Design
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Molecular Conformation
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Norepinephrine / chemistry*
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Norepinephrine / metabolism
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Norepinephrine Plasma Membrane Transport Proteins / chemical synthesis*
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Norepinephrine Plasma Membrane Transport Proteins / pharmacology*
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Oxygen / chemistry*
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Propylamines / chemistry
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Propylamines / pharmacology
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Structure-Activity Relationship
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Symporters / chemistry
Substances
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Adrenergic Uptake Inhibitors
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Norepinephrine Plasma Membrane Transport Proteins
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Propylamines
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Symporters
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Atomoxetine Hydrochloride
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Cytochrome P-450 CYP2D6
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Oxygen
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Norepinephrine