Discovery of 1-Butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A Novel Positive Allosteric Modulator of the Metabotropic Glutamate 2 Receptor
| Autor: | Pype Stefan Maria Christiaan, Andrés A. Trabanco, Wilhelmus Drinkenburg, Abdelah Ahnaou, María Lourdes Linares, José Manuel Alonso, Guillaume Albert Jacques Duvey, Ana Isabel de Lucas, Sonia Poli, Jean-Philippe Rocher, Terry Patrick Finn, Juan Antonio Vega, Claire Mackie, David J. Gallacher, Jesús Alcázar, Encarnación Matesanz, José Ignacio Andrés, Daniel Oehlrich, Hilde Lavreysen, Robert Johannes Lütjens, Gregor James Macdonald, José María Cid, Gary Tresadern |
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| Rok vydání: | 2014 |
| Předmět: |
Male
ERG1 Potassium Channel Patch-Clamp Techniques Allosteric modulator Pyridones Stereochemistry Allosteric regulation hERG CHO Cells Receptors Metabotropic Glutamate Rats Sprague-Dawley Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Cricetulus Dogs Allosteric Regulation Piperidines In vivo Drug Discovery Animals Humans Potency Structure–activity relationship Wakefulness biology Chemistry Electroencephalography Ether-A-Go-Go Potassium Channels HEK293 Cells Metabotropic receptor Anti-Anxiety Agents biology.protein Molecular Medicine Sleep Lead compound Antipsychotic Agents |
| Zdroj: | Journal of Medicinal Chemistry. 57:6495-6512 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm500496m |
| Popis: | We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders. |
| Databáze: | OpenAIRE |
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