title: Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.
abstract: 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.
authors.affiliation: Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, 45007-Toledo, Spain. jcid@its.jnj.com
authors.forename: Jose María
authors.initials: JM
authors.lastname: Cid
authors.forename: Guillaume
authors.initials: G
authors.lastname: Duvey
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.forename: Vanthea
authors.initials: V
authors.lastname: Nhem
authors.forename: Rocco
authors.initials: R
authors.lastname: Furnari
authors.forename: Philippe
authors.initials: P
authors.lastname: Cluzeau
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: José Manuel
authors.initials: JM
authors.lastname: Alonso
authors.forename: María Lourdes
authors.initials: ML
authors.lastname: Linares
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Andrés
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Poli
authors.forename: Robert
authors.initials: R
authors.lastname: Lutjens
authors.forename: Hassan
authors.initials: H
authors.lastname: Himogai
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rocher
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: Andrés A
authors.initials: AA
authors.lastname: Trabanco
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000378:metabolism; D004357:Drug Synergism; D000072237:ERG1 Potassium Channel; D004569:Electroencephalography; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D012895:Sleep, REM / Q000187:drug effects; D013329:Structure-Activity Relationship; D014851:Wakefulness
chemical_list: C573299:1-butyl-4-(3-fluoro-4-(2-methylpyridin-4-yloxy)phenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D009570:Nitriles; D011728:Pyridones; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2