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

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

共 24 条

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DRUG METABOLISM AND DISPOSITION, 2013, 41 (09) : 1626 - 1641
[2] Rescue of dendritic spine phenotype in Fmr1 KO mice with the mGluR5 antagonist AFQ056/Mavoglurant
Pop, Andreea S.
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de Esch, Celine E. F.
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PSYCHOPHARMACOLOGY, 2014, 231 (06) : 1227 - 1235
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Aaron Isaacs
Fabrizio Gasparini
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Psychopharmacology, 2014, 231 : 1227 - 1235
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MOVEMENT DISORDERS, 2013, 28 : S162 - S162
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Chakraborty, Abhijit
Rouzade-Dominguez, Marie-Laure
Neelakantham, Srikanth
Jakab, Annamaria
Mensinga, Tjeert
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Woessner, Ralph
Ufer, Mike
INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS, 2015, 53 (07) : 550 - 556
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BMC MEDICAL GENETICS, 2012, 13
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Zerbi, Valerio
Markicevic, Marija
Gasparini, Fabrizio
Schroeter, Aileen
Rudin, Markus
Wenderoth, Nicole
NEUROIMAGE, 2019, 191 : 392 - 402

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