title: Discovery and Preclinical Characterization of 3-((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications.
abstract: Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Galambos
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Bielik
authors.affiliation: Institute of Chemistry, Saint Petersburg State University , 26 Universitetskii Prospekt, Peterhof, 198504 Russia.
authors.forename: Mikhail
authors.identifier: 0000-0002-0200-4772
authors.initials: M
authors.lastname: Krasavin
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences , 2 Magyar tudósok körútja, Budapest, 1117 Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Orgován
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Domány
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Nógrádi
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Wágner
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: György T
authors.initials: GT
authors.lastname: Balogh
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Béni
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Kóti
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szakács
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Amrita
authors.initials: A
authors.lastname: Bobok
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Kolok
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Mónika L
authors.initials: ML
authors.lastname: Mikó-Bakk
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Vastag
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sághy
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Laszy
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Attila Sándor
authors.initials: AS
authors.lastname: Halász
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Ottilia
authors.initials: O
authors.lastname: Balázs
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Gál
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: István
authors.identifier: 0000-0002-5336-2828
authors.initials: I
authors.lastname: Greiner
authors.affiliation: Gedeon Richter Plc , 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szombathelyi
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences , 2 Magyar tudósok körútja, Budapest, 1117 Hungary.
authors.forename: György M
authors.identifier: 0000-0003-1039-7809
authors.initials: GM
authors.lastname: Keserű
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D005260:Female; D054879:Halogenation; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*
chemical_list: D014151:Anti-Anxiety Agents; D009570:Nitriles; D011804:Quinolines; D064529:Receptor, Metabotropic Glutamate 5; C014356:benzonitrile