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

被引:47
|
作者
Vranesic, Ivo [1 ]
Ofner, Silvio [1 ]
Flor, Peter Josef [1 ]
Bilbe, Graeme [1 ]
Bouhelal, Rochdi [1 ]
Enz, Albert [1 ]
Desrayaud, Sandrine [1 ]
McAllister, Kevin [1 ]
Kuhn, Rainer [1 ]
Gasparini, Fabrizio [1 ]
机构
[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland
关键词
mGluR5; Non-competitive; Allosteric; Antagonist; STRESS-INDUCED HYPERTHERMIA; ACUTE ISCHEMIC-STROKE; NONCOMPETITIVE ANTAGONISTS; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; ANXIOLYTIC-LIKE; POTENT; MPEP; 2-METHYL-6-(PHENYLETHYNYL)PYRIDINE; CHEMISTRY;
D O I
10.1016/j.bmc.2014.09.033
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5790 / 5803
页数:14
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