Abstract
Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep-wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.
MeSH terms
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Administration, Oral
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Allosteric Regulation
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Animals
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Biological Availability
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Brain / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line
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Cricetinae
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Cricetulus
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Cytochrome P-450 Enzyme Inhibitors
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacokinetics
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Imidazoles / pharmacology
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Ion Channels / antagonists & inhibitors
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Male
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Mice
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Microsomes, Liver / metabolism
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Radioligand Assay
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Rats
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Receptors, Metabotropic Glutamate / agonists
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Receptors, Metabotropic Glutamate / antagonists & inhibitors
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Receptors, Metabotropic Glutamate / metabolism*
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Sleep / drug effects
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Structure-Activity Relationship
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Wakefulness / drug effects
Substances
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8-chloro-7-(7-chloro-1H-indol-5-yl)-3-(2,2,2-trifluoroethyl)imidazo(1,2-a)pyridine
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Bridged Bicyclo Compounds, Heterocyclic
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Cytochrome P-450 Enzyme Inhibitors
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Imidazoles
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Indoles
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Ion Channels
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Pyridines
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor 2