2. Academic Validation
  3. 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

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

  • J Med Chem. 2015 Feb 12;58(3):1358-71. doi: 10.1021/jm501642c.
Georg Jaeschke 1,  Sabine Kolczewski,  Will Spooren,  Eric Vieira,  Nadia Bitter-Stoll,  Patrick Boissin,  Edilio Borroni,  Bernd Büttelmann,  Simona Ceccarelli,  Nicole Clemann,  Beatrice David,  Christoph Funk,  Wolfgang Guba,  Anthony Harrison,  Thomas Hartung,  Michael Honer,  Jörg Huwyler,  Martin Kuratli,  Urs Niederhauser,  Axel Pähler,  Jens-Uwe Peters,  Ann Petersen,  Eric Prinssen,  Antonio Ricci,  Daniel Rueher,  Marianne Rueher,  Manfred Schneider,  Paul Spurr,  Theodor Stoll,  Daniel Tännler,  Jürgen Wichmann,  Richard H Porter,  Joseph G Wettstein,  Lothar Lindemann
Affiliations

Affiliation

  • 1 Discovery Chemistry, Therapeutic Modalities, ‡Discovery Neuroscience, Neuroscience, Ophthalmology & Rare Diseases (NORD), §Communications, ∥Pharmaceutical Sciences, ⊥Molecular Design and Chemical Biology, Therapeutic Modalities, #Small Molecules Process Research and Synthesis, Therapeutic Modalities, ∞Infections Diseases, and ×Operations for Neuroscience, Ophthalmology, and Rare Diseases (NORD), Innovation Center Basel, Roche Pharmaceutical Research and Early Development , Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
PMID: 25565255 DOI: 10.1021/jm501642c
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.

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