1. Academic Validation
  2. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization

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

  • Bioorg Med Chem. 2014 Nov 1;22(21):5790-803. doi: 10.1016/j.bmc.2014.09.033.
Ivo Vranesic 1 Silvio Ofner 1 Peter Josef Flor 1 Graeme Bilbe 1 Rochdi Bouhelal 1 Albert Enz 1 Sandrine Desrayaud 1 Kevin McAllister 1 Rainer Kuhn 1 Fabrizio Gasparini 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. Electronic address: [email protected].
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.

Keywords

Allosteric; Antagonist; Non-competitive; mGluR5.

Figures
Products