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

被引：49

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 21期

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

页码：5790 / 5803

页数：14