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

Ofner, Silvio and Vranesic, Ivan-Toma and Bilbe, Graeme and Bouhelal, Rochdi and Ertl, Peter and hart, terry and rasetti, vittorio and Mcallister, Kevin and Kuhn, Rainer R and Gasparini, Fabrizio (2014) AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: Identification, SAR and pharmacological characterization. Bioorganic and Medicinal Chemistry, 22 (21). pp. 5790-5803. ISSN 1464-3391

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 IC<inf>50</inf> 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
Keywords: Allosteric Antagonist mGluR5 Non-competitive
Date Deposited: 25 Oct 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/6560

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