Abstract
The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.
MeSH terms
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Alkylation
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Animals
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Chemical Phenomena
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Chemistry, Physical
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Chromones
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Cross Reactions
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Dose-Response Relationship, Drug
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ERG1 Potassium Channel
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Ether-A-Go-Go Potassium Channels / pharmacology
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Heart Rate / drug effects
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / pharmacology
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Humans
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Mice
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Piperidines / chemical synthesis*
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Piperidines / pharmacology*
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Receptors, Somatostatin / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Chromones
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Cytochrome P-450 Enzyme Inhibitors
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ERG1 Potassium Channel
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Enzyme Inhibitors
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Ether-A-Go-Go Potassium Channels
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Heterocyclic Compounds
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KCNH2 protein, human
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MCHR1 protein, human
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Piperidines
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Receptors, Somatostatin
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human