mGlu5受体变构拮抗剂CTEP | 871362-31-1

• 物质功能分类: 生物化工 - 抑制剂 - 神经信号通路(Neuronal Signaling)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 中文名称: mGlu5受体变构拮抗剂CTEP
• 中文别名: 2-氯-4-[[2,5-二甲基-1-[4-(三氟甲氧基)苯基]-1H-咪唑-4-基]乙炔基]吡啶
• 英文名称: CTEP
• 英文别名: [2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine]；[3H]-CTEP；2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine
• CAS: 871362-31-1
• 化学式: C₁₉H₁₃ClF₃N₃O
• 分子量: 391.78
• InChiKey: GOHCTCOGYKAJLZ-UHFFFAOYSA-N

物化性质

• 沸点：
  523.0±60.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)
• 溶解度：
  不溶于乙醇；不溶于水； DMSO 中≥19.6 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  39.9
• 氢给体数：
  0
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P264,P270,P301+P312,P330
• 危险性描述：
  H302,H315,H320,H335

制备方法与用途

生物活性

CTEP（RO4956371）是一种新型、长效且口服生物有效的mGlu5受体变构拮抗剂，其IC50值为2.2 nM，在选择性上比作用于其他mGlu受体高出近1000倍。

靶点

Target	Value
mGlu5	2.2 nM

体外研究

CTEP在稳定表达人源mGlu5的HEK293细胞中，能够有效抑制quisqualate诱导的Ca2+ 内流。

体内研究

当剂量为0.1 mg/kg和0.3 mg/kg时，CTEP对治疗小鼠的焦虑有显著效果。在0.3 mg/kg和1.0 mg/kg剂量下进行Vogel饮水冲突测试时，CTEP能使大鼠的饮水次数显著增加；而在低剂量组中没有观察到此效应。CTEP的口服半衰期为18小时，在小鼠血浆中的药物浓度比值（B/P）约为2.6。

用盐溶液或吐温溶液悬浮配制CTEP，按4.5 mg/kg和8.7 mg/kg单独口服剂量喂给C57BL/6成年小鼠后，CTEP迅速被吸收，在约30分钟后达到最大药效。连续每天两次口服2 mg/kg的CTEP，每48小时一次，持续治疗两个月，可使脑内CTEP暴露量保持在最低水平，约为240 ng/g。

给小鼠每日两次口服2 mg/kg剂量的CTEP可以有效替代mGlu5受体功能。在Fmr1敲除的小鼠中，通过口服2 mg/kg CTEP处理能够纠正海马长时程抑制效应、过多蛋白质表达及听源性癫痫发作等问题。

反应信息

• 作为产物：
  描述：

  3-chloro-2-(2-chloropyridin-4-yl)-3-[2,5-dimethyl-1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]propenal 在 potassium tert-butylate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.0h， 以27%的产率得到mGlu5受体变构拮抗剂CTEP
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jm501642c

文献信息

• [EN] PYRIDIN-4-YL-ETHYNYL-IMIDAZOLES AND PYRAZOLES AS MGLU5 RECEPTOR ANTAGONISTS<br/>[FR] PYRIDIN-4-YL-ETHYNYL-IMIDAZOLES ET PYRAZOLES, ANTAGONISTES DU RECEPTEUR MGLUR5
  申请人：HOFFMANN LA ROCHE

  公开号：WO2005118568A1

  公开（公告）日：2005-12-15

  The present invention relates to diazole derivatives of the general formula (I) wherein A, E, R1, Wand R3 are as defined in the claims and description, their use for the preparation of medicaments for treating diseases and processes for preparing them.

  本发明涉及一般式(I)的噻唑烯衍生物，其中A、E、R1、W和R3如权利要求和描述中定义的那样，它们用于制备治疗疾病的药物和制备过程。
• METHODS FOR THE TREATMENT OF GERD WITH MGLUR5 ANTAGONISTS
  申请人：Jaeschke Georg

  公开号：US20090054490A1

  公开（公告）日：2009-02-26

  The present invention relates to methods for the treatment, prevention and/or delay of progression of gastro-esophageal reflux disease (GERD) by administering compounds that act as antagonists of metabotropic glutamate type-5 receptors (mGluR5 receptor antagonists), for example compounds of formula (I) wherein A, E, R 1 , R 2 , R 2 and R 4 are as defined in the specification.

  本发明涉及通过给予作为代谢型谷氨酸5型受体拮抗剂（mGluR5受体拮抗剂）的化合物来治疗、预防和/或延缓胃食管反流病（GERD）的进展的方法，例如具有以下结构的化合物（I）其中A、E、R1、R2、R3和R4如规范中定义的那样。
• Diazole derivatives
  申请人：Buettelmann Bernd

  公开号：US20060030559A1

  公开（公告）日：2006-02-09

  The present invention relates to diazole derivatives of the general formula wherein A, E, R 1 , R 2 and R 3 are as defined in application and pharmaceutical compositions containing them. The invention also relates to use of such compounds for the treatment of diseases mediated by the metabotropic glutamate receptors (mGluR), such as anxiety, chronic and acute pain, protection against liver damage, urinary incontinence, obesity, Fragile-X and autism, Alzheimer's disease, epilepsy, schizophrenia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDs, and Parkinson's disease.

  本发明涉及一般式为的二唑类衍生物，其中A，E，R1，R2和R3如申请中所定义，并且含有它们的药物组合物。本发明还涉及使用这种化合物治疗由代谢型谷氨酸受体（mGluR）介导的疾病，例如焦虑，慢性和急性疼痛，保护肝脏损伤，尿失禁，肥胖症，脆性X和自闭症，阿尔茨海默病，癫痫，精神分裂症，缺血，亨廷顿舞蹈症，肌萎缩性侧索硬化（ALS），由艾滋病引起的痴呆症以及帕金森病。
• DIAZOLE DERIVATIVES
  申请人：Buettelmann Bernd

  公开号：US20100048569A1

  公开（公告）日：2010-02-25

  The present invention relates to diazole derivatives of the general formula wherein A, E, R 1 , R 2 and R 3 are as defined in application and pharmaceutical compositions containing them. The invention also relates to use of such compounds for the treatment of diseases mediated by the metabotropic glutamate receptors (mGluR), such as anxiety, chronic and acute pain, protection against liver damage, urinary incontinence, obesity, Fragile-X and autism, Alzheimer's disease, epilepsy, schizophrenia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDs, and Parkinson's disease.

  本发明涉及一般式为的二唑衍生物，其中A、E、R1、R2和R3如申请中所定义，并且包含它们的制药组合物。本发明还涉及使用这种化合物治疗通过代谢型谷氨酸受体（mGluR）介导的疾病，例如焦虑、慢性和急性疼痛、保护肝损伤、尿失禁、肥胖症、脆性X和自闭症、阿尔茨海默病、癫痫、精神分裂症、缺血、亨廷顿舞蹈症、肌萎缩性侧索硬化症（ALS）、由艾滋病引起的痴呆症和帕金森病。
• Pharmaceutical compositions of metabotropic glutamate 5 receptor (MGLU5) antagonists
  申请人：F. Hoffmann-La Roche AG

  公开号：EP2808022A1

  公开（公告）日：2014-12-03

  Pharmaceutical compositions of metabotropic glutamate 5 receptor (mGlu5) antagonists or a pharmacologically acceptable salt thereof are disclosed. The compositions contain the therapeutic active compound with non-ionic polymer and ionic polymer, binder and fillers in matrix tablet. The compositions provide a pH-independent in vitro release profile with NMT 70 % in one hour, NMT 85 % in 4 hour, and NLT 80 % in 8 hours. The compositions are useful for the treatment of CNS disorders, such as Treatment-Resistant Depression (TRD) and Fragile X Syndrome.

  本发明公开了代谢谷氨酸 5 受体（mGlu5）拮抗剂或其药理上可接受的盐的药物组合物。这些组合物在基质片剂中含有治疗活性化合物、非离子聚合物和离子聚合物、粘合剂和填料。该组合物具有与 pH 值无关的体外释放特性，1 小时内的 NMT 释放率为 70%，4 小时内的 NMT 释放率为 85%，8 小时内的 NLT 释放率为 80%。该组合物可用于治疗中枢神经系统疾病，如治疗耐受性抑郁症（TRD）和脆性 X 综合征。