title: 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.
abstract: 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.
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Cid
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.forename: Guillaume
authors.initials: G
authors.lastname: Duvey
authors.forename: Robert
authors.initials: R
authors.lastname: Lütjens
authors.forename: Terry
authors.initials: T
authors.lastname: Finn
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rocher
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Vega
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: de Lucas
authors.forename: Encarnación
authors.initials: E
authors.lastname: Matesanz
authors.forename: María Lourdes
authors.initials: ML
authors.lastname: Linares
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Jesús
authors.initials: J
authors.lastname: Alcazar
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Alonso
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.forename: Daniel
authors.initials: D
authors.lastname: Oehlrich
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: Abdelah
authors.initials: A
authors.lastname: Ahnaou
authors.forename: Wilhelmus
authors.initials: W
authors.lastname: Drinkenburg
authors.forename: Claire
authors.initials: C
authors.lastname: Mackie
authors.forename: Stefan
authors.initials: S
authors.lastname: Pype
authors.forename: David
authors.initials: D
authors.lastname: Gallacher
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D003412:Cricetulus; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004569:Electroencephalography; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects; D013329:Structure-Activity Relationship; D014851:Wakefulness / Q000187:drug effects
chemical_list: C000594993:1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone; D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010880:Piperidines; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2