title: Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs.
abstract: Here we report the discovery and early SAR of a series of mGluR5 negative allosteric modulators (NAMs). Starting from a moderately active HTS hit we synthesized 3,5-disubstituted-oxadiazoles and tetrazoles as mGluR5 NAMs. Based on the analysis of ligand efficiency and lipophilic efficiency metrics we identified a promising lead candidate as a starting point for further optimization.
authors.affiliation: Gedeon Richter Plc, Budapest, Hungary. g.wagner@richter.hu
authors.forename: Gábor
authors.initials: G
authors.lastname: Wágner
authors.forename: Csaba
authors.initials: C
authors.lastname: Wéber
authors.forename: Olga
authors.initials: O
authors.lastname: Nyéki
authors.forename: Katalin
authors.initials: K
authors.lastname: Nógrádi
authors.forename: Attila
authors.initials: A
authors.lastname: Bielik
authors.forename: László
authors.initials: L
authors.lastname: Molnár
authors.forename: Amrita
authors.initials: A
authors.lastname: Bobok
authors.forename: Attila
authors.initials: A
authors.lastname: Horváth
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Sándor
authors.initials: S
authors.lastname: Kolok
authors.forename: József
authors.initials: J
authors.lastname: Nagy
authors.forename: Dalma
authors.initials: D
authors.lastname: Kurkó
authors.forename: Krisztina
authors.initials: K
authors.lastname: Gál
authors.forename: István
authors.initials: I
authors.lastname: Greiner
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szombathelyi
authors.forename: György M
authors.initials: GM
authors.lastname: Keseru
authors.forename: György
authors.initials: G
authors.lastname: Domány
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C578935:GRM5 protein, human; D008024:Ligands; D010069:Oxadiazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013777:Tetrazoles