Abstract
The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.
MeSH terms
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Atomoxetine Hydrochloride
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Combinatorial Chemistry Techniques
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Cytochrome P-450 CYP2D6 Inhibitors*
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Drug Design
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Humans
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Indans / chemical synthesis*
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Indans / chemistry
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Indans / pharmacology*
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Inhibitory Concentration 50
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Microsomes, Liver / metabolism
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Molecular Structure
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Neurotransmitter Uptake Inhibitors / chemical synthesis*
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Neurotransmitter Uptake Inhibitors / chemistry
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Neurotransmitter Uptake Inhibitors / pharmacology*
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Norepinephrine / antagonists & inhibitors*
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Propylamines / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Cytochrome P-450 CYP2D6 Inhibitors
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Indans
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Neurotransmitter Uptake Inhibitors
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Propylamines
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Atomoxetine Hydrochloride
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Norepinephrine