Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators: Discovery of 2-Chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (Basimglurant, RO4917523), a Promising Novel Medicine for Psychiatric Diseases

Jaeschke, Georg and Kolczewski, Sabine and Spooren, Will and Vieira, Eric and Bitter-Stoll, Nadia and Boissin, Patrick and Borroni, Edilio and Büttelmann, Bernd and Ceccarelli, Simona and Clemann, Nicole and David, Beatrice and Funk, Christoph and Guba, Wolfgang and Harrison, Anthony and Hartung, Thomas and Honer, Michael and Huwyler, Jörg and Kuratli, Martin and Niederhauser, Urs and Pähler, Axel and Peters, Jens-Uwe and Petersen, Ann and Prinssen, Eric and Ricci, Antonio and Rueher, Daniel and Rueher, Marianne and Schneider, Manfred and Spurr, Paul and Stoll, Theodor and Tännler, Daniel and Wichmann, Jürgen and Porter, Richard H. and Wettstein, Joseph G. and Lindemann, Lothar. (2015) Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators: Discovery of 2-Chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (Basimglurant, RO4917523), a Promising Novel Medicine for Psychiatric Diseases. Journal of medicinal chemistry, 58 (3). pp. 1358-1371.

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Official URL: http://edoc.unibas.ch/40938/

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Abstract

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.

Faculties and Departments:	05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmaceutical Technology (Huwyler)
UniBasel Contributors:	Huwyler, Jörg
Item Type:	Article, refereed
Article Subtype:	Research Article
Publisher:	American Chemical Society
ISSN:	0022-2623
Note:	Publication type according to Uni Basel Research Database: Journal article
Identification Number:	doi: 10.1021/jm501642c pmid: 25565255
Last Modified:	11 Aug 2016 08:30
Deposited On:	11 Aug 2016 08:30

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