RESUMO
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.
Assuntos
Indóis/química , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Discinesia Induzida por Medicamentos/tratamento farmacológico , Meia-Vida , Ensaios de Triagem em Larga Escala , Humanos , Hipertermia Induzida , Indóis/farmacocinética , Indóis/farmacologia , Indóis/uso terapêutico , Levodopa/toxicidade , Masculino , Camundongos , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis of a new potent, subtype-selective radioligand [(3)H]-M-MPEP (2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine) and its in vitro pharmacological characteristics are described. Science Ltd.
