title: Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators.
abstract: Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.
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: 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: Gedeon Richter Plc, 19-21 Gyömrői út, Budapest, 1103 Hungary. Electronic address: gy.domany@richter.hu.
authors.forename: György
authors.initials: G
authors.lastname: Domány
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: Béni
authors.affiliation: Gedeon Richter Plc, 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Áron
authors.initials: Á
authors.lastname: Szigetvári
authors.affiliation: Gedeon Richter Plc, 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Sánta
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: Amrita
authors.initials: A
authors.lastname: Bobok
authors.affiliation: Gedeon Richter Plc, 19-21 Gyömrői út, Budapest, 1103 Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
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: Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Prospekt, Peterhof 198504 Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Krasavin
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.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. Electronic address: gy.keseru@ttk.mta.hu.
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000586:Amination; D000818:Animals; D006801:Humans; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D010879:Piperazines; D011804:Quinolines; D064529:Receptor, Metabotropic Glutamate 5
keywords: 4-amino-3-arylsulfonyl-quinolines; Negative allosteric modulator; Optimization; Parallel synthesis; mGlu(5) receptor