AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization.
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.
['Vranesic|Ivo|I|', 'Ofner|Silvio|S|', 'Flor|Peter Josef|PJ|', 'Bilbe|Graeme|G|', 'Bouhelal|Rochdi|R|', 'Enz|Albert|A|', 'Desrayaud|Sandrine|S|', 'McAllister|Kevin|K|', 'Kuhn|Rainer|R|', 'Gasparini|Fabrizio|F|']
D000818:Animals D001921:Brain D004409:Dyskinesia, Drug-Induced D006207:Half-Life D057166:High-Throughput Screening Assays D006801:Humans D006979:Hyperthermia, Induced D007211:Indoles D007980:Levodopa D008297:Male D051379:Mice D011485:Protein Binding D011725:Pyridines D051381:Rats D017207:Rats, Sprague-Dawley D064529:Receptor, Metabotropic Glutamate 5 D013329:Structure-Activity Relationship
mGluR5 Antagonist Non-competitive Allosteric