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

Vranesic, Ivan-Toma and Ofner, Silvio and Flor, Peter Josef and Bilbe, Graeme and Bouhelal, Rochdi and Enz, Albert and Desrayaud, Sandrine and Mcallister, Kevin and 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

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