title: AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization.
abstract: Here we describe the identification, structure-activity relationship and the initial pharmacological characterization of AFQ056/mavoglurant, a structurally novel, non-competitive mGlu5 receptor antagonist. AFQ056/mavoglurant was identified by chemical derivatization of a lead compound discovered in a HTS campaign. In vitro, AFQ056/mavoglurant had an IC50 of 30 nM in a functional assay with human mGluR5 and was selective over the other mGluR subtypes, iGluRs and a panel of 238 CNS relevant receptors, transporter or enzymes. In vivo, AFQ056/mavoglurant showed an improved pharmacokinetic profile in rat and efficacy in the stress-induced hyperthermia test in mice as compared to the prototypic mGluR5 antagonist MPEP. The efficacy of AFQ056/mavoglurant in humans has been assessed in L-dopa induced dyskinesia in Parkinson's disease and Fragile X syndrome in proof of principle clinical studies.
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Ivo
authors.initials: I
authors.lastname: Vranesic
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Silvio
authors.initials: S
authors.lastname: Ofner
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Peter Josef
authors.initials: PJ
authors.lastname: Flor
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Graeme
authors.initials: G
authors.lastname: Bilbe
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Rochdi
authors.initials: R
authors.lastname: Bouhelal
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Albert
authors.initials: A
authors.lastname: Enz
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Kevin
authors.initials: K
authors.lastname: McAllister
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuhn
authors.affiliation: Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: fabrizio.gasparini@novartis.com.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D006207:Half-Life; D057166:High-Throughput Screening Assays; D006801:Humans; D006979:Hyperthermia, Induced; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D007980:Levodopa / Q000633:toxicity; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; C581397:mavoglurant
keywords: Allosteric; Antagonist; Non-competitive; mGluR5