title: Tetrahydronaphthyridine and dihydronaphthyridinone ethers as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu₅).
abstract: Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Turlington
authors.forename: Chrysa
authors.initials: C
authors.lastname: Malosh
authors.forename: Jon
authors.initials: J
authors.lastname: Jacobs
authors.forename: Jason T
authors.initials: JT
authors.lastname: Manka
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Noetzel
authors.forename: Paige N
authors.initials: PN
authors.lastname: Vinson
authors.forename: Satyawan
authors.initials: S
authors.lastname: Jadhav
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Herman
authors.forename: Hilde
authors.initials: H
authors.lastname: Lavreysen
authors.forename: Claire
authors.initials: C
authors.lastname: Mackie
authors.forename: José M
authors.initials: JM
authors.lastname: Bartolomé-Nebreda
authors.forename: Susana
authors.initials: S
authors.lastname: Conde-Ceide
authors.forename: M Luz
authors.initials: ML
authors.lastname: Martín-Martín
authors.forename: Han Min
authors.initials: HM
authors.lastname: Tong
authors.forename: Silvia
authors.initials: S
authors.lastname: López
authors.forename: Gregor J
authors.initials: GJ
authors.lastname: MacDonald
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D009287:Naphthyridines; D064529:Receptor, Metabotropic Glutamate 5