Discovery of 1,5-Disubstituted Pyridones: A New Class of Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor
| Autor: | Philippe Cluzeau, Hassan Julien Imogai, Mark Epping-Jordan, Alexandre Raux, Guillaume Albert Jacques Duvey, Jean-Philippe Rocher, Gregor James Macdonald, José María Cid, Ana Isabel de Lucas, Juan Antonio Vega, Vanthea Nhem, Francis Derouet, Gary Tresadern, Andrés A. Trabanco, Christelle Boléa, José Ignacio Andrés, Robert Johannes Lütjens, Daniel Oehlrich, Karim Macary, Encarnación Matesanz, Hilde Lavreysen, Terry Patrick Finn, Sonia Poli, Jessica Muller, María Lourdes Linares, Nicolas Poirier, Francoise Girard, Julen Oyarzabal, Emilie Chamelot, Emmanuel Le Poul |
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| Rok vydání: | 2010 |
| Předmět: |
Allosteric modulator
Pyridines Pyridones Physiology Stereochemistry Cognitive Neuroscience Allosteric regulation Drug Evaluation Preclinical Motor Activity Receptors Metabotropic Glutamate Biochemistry Bridged Bicyclo Compounds Mice Structure-Activity Relationship Allosteric Regulation Drug Stability In vivo Excitatory Amino Acid Agonists Animals Humans Amino Acids Receptor ADME Sulfonamides Molecular Structure Chemistry Cell Biology General Medicine Recombinant Proteins In vitro Metabotropic receptor Metabotropic glutamate receptor 2 Hydrophobic and Hydrophilic Interactions |
| Zdroj: | ACS Chemical Neuroscience. 1:788-795 |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/cn1000638 |
| Popis: | The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep–wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories. |
| Databáze: | OpenAIRE |
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