title: 4-Aryl-3-arylsulfonyl-quinolines as negative allosteric modulators of metabotropic GluR5 receptors: From HTS hit to development candidate.
abstract: High throughput screening of our corporate compound library followed by hit-to-lead development resulted in a 4-aryl-3-arylsulfonyl-quinoline derivative lead (2) with mGluR5 negative allosteric modulator activity. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modifications at the three targeted regions of the lead structure resulted in compounds with nanomolar affinity and acceptable metabolic stability. One of the most promising compounds (3), showing excellent in vivo efficacy, was selected for preclinical development and subsequent phase I clinical studies.
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary. Electronic address: J.Galambos@richter.hu.
authors.forename: János
authors.initials: J
authors.lastname: Galambos
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Domány
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Nógrádi
authors.affiliation: Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Gábor
authors.initials: G
authors.lastname: Wágner
authors.affiliation: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Amrita
authors.initials: A
authors.lastname: Bobok
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Kolok
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Mónika L
authors.initials: ML
authors.lastname: Mikó-Bakk
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Vastag
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sághy
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Kóti
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Szakács
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Béni
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Gál
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szombathelyi
authors.affiliation: Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Greiner
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002493:Central Nervous System Diseases / Q000209:etiology; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011804:Quinolines; D064529:Receptor, Metabotropic Glutamate 5; C037219:quinoline
keywords: 4-Aryl-3-arylsulfonyl-quinolines; Negative allosteric modulator; mGluR5