Vranesic, Ivan-Toma, Ofner, Silvio, Flor, Peter Josef, Bilbe, Graeme, Bouhelal, Rochdi, Enz, Albert, Desrayaud, Sandrine, Mcallister, Kevin, Kuhn, Rainer and Gasparini, Fabrizio (2014) AFQ056/Mavoglurant a novel clinically effective mGluR5 antagonist: Identification, SAR and pharmacological characterization. Bioorganic Medicinal Chemistry, 22 (21). pp. 5790-5803. ISSN 09680896

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.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:12
Last Modified:	04 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22319