title: 1,3,5-Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu2/3Receptors.
abstract: The metabotropic glutamate subtype 2 (mGlu2) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu2receptor function with a negative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high-throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu2NAM GTPγS assay. In addition to SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu2receptor occupancy. Finally, to obtain improved drug-like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high in vitro potency.
authors.affiliation: Neuroscience, Janssen Research & Development, Jarama 75A, 45007, Toledo, Spain.
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Gool
authors.affiliation: Neuroscience, Janssen Research & Development, Jarama 75A, 45007, Toledo, Spain.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Alonso De Diego
authors.affiliation: Neuroscience, Janssen Research & Development, Jarama 75A, 45007, Toledo, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Delgado
authors.affiliation: Neuroscience, Janssen Research & Development, Jarama 75A, 45007, Toledo, Spain.
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.affiliation: NovAliX Pharma, Jarama 75A, 45007, Toledo, Spain.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jourdan
authors.affiliation: Neuroscience, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: Macdonald
authors.affiliation: Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Marijke
authors.initials: M
authors.lastname: Somers
authors.affiliation: Neuroscience, Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Ver Donck
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2
keywords: ex vivo occupancy; metabotropic glutamate 2 receptor; negative allosteric modulators; pyrazoles