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 Jörg, Kuratli Martin, Niederhauser Urs, Pähler Axel, Peters Jens-Uwe, Petersen Ann, Prinssen Eric, Ricci Antonio, Rueher Daniel, Rueher Marianne, Schneider Manfred, Spurr Paul, Stoll Theodor, Tännler Daniel, Wichmann Jürgen, Porter Richard H, Wettstein Joseph G, Lindemann Lothar
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.
J Med Chem. 2015 Feb 12;58(3):1358-71. doi: 10.1021/jm501642c. Epub 2015 Feb 2.
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.
代谢型谷氨酸受体5（mGlu5）的负变构调节剂（NAMs）具有治疗多种精神疾病的潜力，这些疾病包括抑郁症、脆性X综合征（FXS）、焦虑症、强迫症以及帕金森病中的左旋多巴诱导的运动障碍。在此，我们报告了将活性较弱的筛选命中化合物1优化为强效且选择性的化合物氯-4-[1-(4-氟苯基)-2,5-二甲基-1H-咪唑-4-基乙炔基]吡啶（巴昔美坦，2）和2-氯-4-((2,5-二甲基-1-(4-(三氟甲氧基)phenyl)-1H-咪唑-4-基)乙炔基)吡啶（CTEP，3）。化合物2在广泛的焦虑测试中均有活性，与地西泮达到相同疗效，但剂量低10至100倍，并且在大鼠和猴子中具有良好的药物代谢动力学性质以及出色的临床前安全性，目前正处于治疗抑郁症和脆性X综合征的II期临床研究阶段。类似物3是首个报道的在啮齿动物中具有长半衰期的mGlu5 NAM，因此是用于小鼠和大鼠慢性研究的理想工具化合物。
