AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: Identification, SAR and pharmacological characterization

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 21; pp. 5790 - 5803
• Main Authors: Vranesic, Ivo, Ofner, Silvio, Flor, Peter Josef, Bilbe, Graeme, Bouhelal, Rochdi, Enz, Albert, Desrayaud, Sandrine, McAllister, Kevin, Kuhn, Rainer, Gasparini, Fabrizio
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2014; Elsevier
• Subjects: Allosteric; Animals; Antagonist; Biochemistry & Molecular Biology; Brain - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dyskinesia, Drug-Induced - drug therapy; Half-Life; High-Throughput Screening Assays; Humans; Hyperthermia, Induced; Indoles - chemistry; Indoles - pharmacokinetics; Indoles - pharmacology; Indoles - therapeutic use; Levodopa - toxicity; Life Sciences & Biomedicine; Male; mGluR5; Mice; Non-competitive; Pharmacology & Pharmacy; Physical Sciences; Protein Binding - drug effects; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacokinetics; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5 - antagonists & inhibitors; Receptor, Metabotropic Glutamate 5 - metabolism; Science & Technology; Structure-Activity Relationship; hmGluR5a; [Ca2+]i; HTS; l-Glu; hmGluR1b; GABAB; mGluR; Non-competitive; Allosteric; sd; SIH; IC50 (EC50); CDZ; PI; FLIPR; Antagonist; 95% CI; mGluR5; P2Y2; MPEP; NONCOMPETITIVE ANTAGONISTS; POTENT; 2-METHYL-6-(PHENYLETHYNYL)PYRIDINE; FUNCTIONAL EXPRESSION; ACUTE ISCHEMIC-STROKE; ANXIOLYTIC-LIKE; CHEMISTRY; MOLECULAR-CLONING; STRESS-INDUCED HYPERTHERMIA
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.09.033

[Display omitted] 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 30nM 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.