Recent Advances in the Design and Development of Novel Negative Allosteric Modulators of MGlu(5)

Overview

Journal ACS Chem Neurosci

Publisher American Chemical Society

Specialty Neurology

Date 2011 Sep 20

PMID 21927649

Citations 27

Authors

Kyle A Emmitte

Affiliations

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Abstract

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu(5)) have remained attractive to researchers as potential therapies for a number of central nervous system related diseases, including anxiety, pain, gastroesophageal reflux disease (GERD), addiction, Parkinson's disease (PD), and fragile X syndrome (FXS). In addition to the many publications with supportive preclinical data with key tool molecules, recent positive reports from the clinic have bolstered the confidence in this approach. During the two year time span from 2009 through 2010, a number of new mGlu(5) NAM chemotypes have been disclosed and discussed in the primary and patent literature. A summary of several efforts representing many diverse chemotypes are presented here, along with a discussion of representative structure activity relationships (SAR) and synthetic approaches to the templates where possible.

Citing Articles

Discovery of 4-(5-Membered)Heteroarylether-6-methylpicolinamide Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5.

Childress E, Capstick R, Crocker K, Ledyard M, Bender A, Maurer M ACS Med Chem Lett. 2024; 15(12):2210-2219.

PMID: 39691522 PMC: 11647725. DOI: 10.1021/acsmedchemlett.4c00481.

From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems.

Carey C, Singh N, Dunn J, Sementa T, Mendez M, Velthuis H Transl Psychiatry. 2022; 12(1):395.

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Sadek K, Ahmed Mekheimer R, Abd-Elmonem M, Elnagdi M Mol Divers. 2019; 23(4):1065-1084.

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Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.

Felts A, Bollinger K, Brassard C, Rodriguez A, Morrison R, Daniels J Bioorg Med Chem Lett. 2018; 29(1):47-50.

PMID: 30446311 PMC: 6295259. DOI: 10.1016/j.bmcl.2018.11.017.

N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents.

Felts A, Rodriguez A, Morrison R, Venable D, Blobaum A, Byers F Bioorg Med Chem Lett. 2016; 26(8):1894-900.

PMID: 26988308 PMC: 4824313. DOI: 10.1016/j.bmcl.2016.03.026.

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