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.
|
Authors | Ivo Vranesic, Silvio Ofner, Peter Josef Flor, Graeme Bilbe, Rochdi Bouhelal, Albert Enz, Sandrine Desrayaud, Kevin McAllister, Rainer Kuhn, Fabrizio Gasparini |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 22
Issue 21
Pg. 5790-803
(Nov 01 2014)
ISSN: 1464-3391 [Electronic] England |
PMID | 25316499
(Publication Type: Journal Article)
|
Copyright | Copyright © 2014 Elsevier Ltd. All rights reserved. |
Chemical References |
- Indoles
- Pyridines
- Receptor, Metabotropic Glutamate 5
- Levodopa
- 6-methyl-2-(phenylethynyl)pyridine
- mavoglurant
|
Topics |
- Animals
- Brain
(metabolism)
- Dyskinesia, Drug-Induced
(drug therapy)
- Half-Life
- High-Throughput Screening Assays
- Humans
- Hyperthermia, Induced
- Indoles
(chemistry, pharmacokinetics, pharmacology, therapeutic use)
- Levodopa
(toxicity)
- Male
- Mice
- Protein Binding
(drug effects)
- Pyridines
(chemistry, metabolism, pharmacokinetics)
- Rats
- Rats, Sprague-Dawley
- Receptor, Metabotropic Glutamate 5
(antagonists & inhibitors, metabolism)
- Structure-Activity Relationship
|