title: Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases.
abstract: Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.
authors.affiliation: Discovery Chemistry, Therapeutic Modalities, ‡Discovery Neuroscience, Neuroscience, Ophthalmology & Rare Diseases (NORD), §Communications, ∥Pharmaceutical Sciences, ⊥Molecular Design and Chemical Biology, Therapeutic Modalities, #Small Molecules Process Research and Synthesis, Therapeutic Modalities, ∞Infections Diseases, and ×Operations for Neuroscience, Ophthalmology, and Rare Diseases (NORD), Innovation Center Basel, Roche Pharmaceutical Research and Early Development , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.forename: Sabine
authors.initials: S
authors.lastname: Kolczewski
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Eric
authors.initials: E
authors.lastname: Vieira
authors.forename: Nadia
authors.initials: N
authors.lastname: Bitter-Stoll
authors.forename: Patrick
authors.initials: P
authors.lastname: Boissin
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: Bernd
authors.initials: B
authors.lastname: Büttelmann
authors.forename: Simona
authors.initials: S
authors.lastname: Ceccarelli
authors.forename: Nicole
authors.initials: N
authors.lastname: Clemann
authors.forename: Beatrice
authors.initials: B
authors.lastname: David
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Guba
authors.forename: Anthony
authors.initials: A
authors.lastname: Harrison
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.forename: Martin
authors.initials: M
authors.lastname: Kuratli
authors.forename: Urs
authors.initials: U
authors.lastname: Niederhauser
authors.forename: Axel
authors.initials: A
authors.lastname: Pähler
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Peters
authors.forename: Ann
authors.initials: A
authors.lastname: Petersen
authors.forename: Eric
authors.initials: E
authors.lastname: Prinssen
authors.forename: Antonio
authors.initials: A
authors.lastname: Ricci
authors.forename: Daniel
authors.initials: D
authors.lastname: Rueher
authors.forename: Marianne
authors.initials: M
authors.lastname: Rueher
authors.forename: Manfred
authors.initials: M
authors.lastname: Schneider
authors.forename: Paul
authors.initials: P
authors.lastname: Spurr
authors.forename: Theodor
authors.initials: T
authors.lastname: Stoll
authors.forename: Daniel
authors.initials: D
authors.lastname: Tännler
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wichmann
authors.forename: Richard H
authors.initials: RH
authors.lastname: Porter
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D003863:Depression / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005600:Fragile X Syndrome / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; C000596770:2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine; D007093:Imidazoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5