Imidazo[1,2-a]pyridines: Orally Active Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor

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 rec...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-03, Vol.55 (6), p.2688-2701
Main Authors: Trabanco, Andrés A, Tresadern, Gary, Macdonald, Gregor J, Vega, Juan Antonio, de Lucas, Ana Isabel, Matesanz, Encarnación, García, Aránzazu, Linares, María Lourdes, Alonso de Diego, Sergio A, Alonso, José Manuel, Oehlrich, Daniel, Ahnaou, Abdelah, Drinkenburg, Wilhelmus, Mackie, Claire, Andrés, José Ignacio, Lavreysen, Hilde, Cid, José María
Format: Article
Language:English
Subjects:
Administration, Oral
Allosteric Regulation
Animals
Biological Availability
Brain - metabolism
Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis
Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics
Bridged Bicyclo Compounds, Heterocyclic - pharmacology
Cell Line
Cricetinae
Cricetulus
Cytochrome P-450 Enzyme Inhibitors
Humans
Imidazoles - chemical synthesis
Imidazoles - pharmacokinetics
Imidazoles - pharmacology
Indoles - chemical synthesis
Indoles - pharmacokinetics
Indoles - pharmacology
Ion Channels - antagonists & inhibitors
Male
Mice
Microsomes, Liver - metabolism
Pyridines - chemical synthesis
Pyridines - pharmacokinetics
Pyridines - pharmacology
Radioligand Assay
Rats
Receptors, Metabotropic Glutamate - agonists
Receptors, Metabotropic Glutamate - antagonists & inhibitors
Receptors, Metabotropic Glutamate - metabolism
Sleep - drug effects
Structure-Activity Relationship
Wakefulness - drug effects
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm201561r