Journal of Medicinal Chemistry p. 1358 - 1371 (2015)
Update date:2022-08-17
Topics:
Jaeschke, Georg
Kolczewski, Sabine
Spooren, Will
Vieira, Eric
Bitter-Stoll, Nadia
Boissin, Patrick
Borroni, Edilio
Büttelmann, Bernd
Ceccarelli, Simona
Clemann, Nicole
David, Beatrice
Funk, Christoph
Guba, Wolfgang
Harrison, Anthony
Hartung, Thomas
Honer, Michael
Huwyler, J?rg
Kuratli, Martin
Niederhauser, Urs
P?hler, Axel
Peters, Jens-Uwe
Petersen, Ann
Prinssen, Eric
Ricci, Antonio
Rueher, Daniel
Rueher, Marianne
Schneider, Manfred
Spurr, Paul
Stoll, Theodor
T?nnler, Daniel
Wichmann, Jürgen
Porter, Richard H.
Wettstein, Joseph G.
Lindemann, Lothar
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.
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