title: Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome.
abstract: Fragile X syndrome (FXS) is the most common monogenic form of inherited mental retardation caused by a trinucleotid repeat expansion and transcriptional shutdown of the FMR1 gene. FXS patients present a complex and often severe neuropsychiatric phenotype yet have mild somatic symptoms, normal life expectancies, and no indications of neurodegeneration. The therapeutic potential of mGlu5 inhibitors was proposed in the 'mGluR theory of FXS' based on early insights into the molecular pathophysiology of FXS. Studies in Fragile X mental retardation 1 (Fmr1) knock-out mice, a widely used disease model, demonstrated that mGlu5 inhibitors can correct a broad range of disease-related phenotypes. Recent clinical trials, however, with two different mGlu5 inhibitors (basimglurant and mavoglurant) showed no therapeutic benefit in FXS patients for reasons as yet unclear.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Scharf
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecules Research, Discovery Chemistry, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Jaeschke
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland. Electronic address: lothar.lindemann@roche.com.
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*
chemical_list: C000596770:2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; C581397:mavoglurant