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: Ivo Vranesic, Silvio Ofner, Peter Josef Flor, Graeme Bilbe, Rochdi Bouhelal, Albert Enz, Sandrine Desrayaud, Kevin McAllister, Rainer Kuhn, Fabrizio Gasparini
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 21 Pg. 5790-803 (Nov 01 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 25316499 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Indoles
• Pyridines
• Receptor, Metabotropic Glutamate 5
• Levodopa
• 6-methyl-2-(phenylethynyl)pyridine
• mavoglurant

Topics

• Animals
• Brain (metabolism)
• Dyskinesia, Drug-Induced (drug therapy)
• Half-Life
• High-Throughput Screening Assays
• Humans
• Hyperthermia, Induced
• Indoles (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Levodopa (toxicity)
• Male
• Mice
• Protein Binding (drug effects)
• Pyridines (chemistry, metabolism, pharmacokinetics)
• Rats
• Rats, Sprague-Dawley
• Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship