Abstract
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
MeSH terms
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Acetylcholine / analysis
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Acetylcholine / metabolism
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Administration, Oral
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Animals
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Area Under Curve
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Benzylidene Compounds / chemistry*
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Benzylidene Compounds / metabolism
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Cytochrome P-450 Enzyme System / metabolism
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Dioxoles / chemistry*
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Dioxoles / pharmacology*
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Drug Design
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Drug Evaluation, Preclinical
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Drug Stability
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Humans
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Macaca fascicularis
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Microdialysis
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Muscarinic Antagonists / blood
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Muscarinic Antagonists / chemistry*
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Muscarinic Antagonists / pharmacology*
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Rats
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Receptor, Muscarinic M2
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Receptors, Muscarinic / drug effects*
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Structure-Activity Relationship
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Sulfones / chemistry*
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Sulfones / pharmacology*
Substances
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1-((3,4-methylenedioxyphenyl)sulfonylphenyl)-1-(1-(1-(n-propylsulfonyl)morpholin-4-yl)morpholin-4-yl)dioxole
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1-((4-methoxyphenyl)sulfonylphenyl)-1(1-(1-(1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole
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1-((4-methoxyphenyl)sulfonylphenyl)-1-(1-(1-(4-fluoro-1-naphthylcarbonyl)morpholin-4-yl)morpholin-4-yl)dioxole
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Benzylidene Compounds
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Dioxoles
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Muscarinic Antagonists
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Receptor, Muscarinic M2
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Receptors, Muscarinic
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Sulfones
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Cytochrome P-450 Enzyme System
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Acetylcholine