7-(3-chloro-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶嗪类
• 英文名称: 7-(3-chloro-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
• 英文别名: 7-[3-Chloro-4-(trifluoromethoxy)phenyl]-4-(pyrimidin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one；7-[3-chloro-4-(trifluoromethoxy)phenyl]-4-(pyrimidin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one
• 化学式: C₂₁H₁₅ClF₃N₃O₃
• 分子量: 449.817
• InChiKey: AHQQBCRDPJYBPY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  64.6
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  7-溴-2,3-二氢-1,4-苯并氮杂卓-5(4H)-酮 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 、 sodium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 甲苯 为溶剂， 反应 8.0h， 生成 7-(3-chloro-4-(trifluoromethoxy)phenyl)-4-(pyrimidin-2-ylmethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  参考文献：
  名称：

  Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late I_Nai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

  摘要：

  Late sodium current (late I-Na) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na-v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-velitricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I-Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anterioior descending, LAD, occlusion in rabbits); with EC50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I-Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

  DOI：

  10.1021/acs.jmedchem.6b00939

文献信息

• Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late <i>I</i>_Nai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties
  作者：Jeff A. Zablocki、Elfatih Elzein、Xiaofen Li、Dmitry O. Koltun、Eric Q. Parkhill、Tetsuya Kobayashi、Ruben Martinez、Britton Corkey、Haibo Jiang、Thao Perry、Rao Kalla、Gregory T. Notte、Oliver Saunders、Michael Graupe、Yafan Lu、Chandru Venkataramani、Juan Guerrero、Jason Perry、Mark Osier、Robert Strickley、Gongxin Liu、Wei-Qun Wang、Lufei Hu、Xiao-Jun Li、Nesrine El-Bizri、Ryoko Hirakawa、Kris Kahlig、Cheng Xie、Cindy Hong Li、Arvinder K. Dhalla、Sridharan Rajamani、Nevena Mollova、Daniel Soohoo、Eve-Irene Lepist、Bernard Murray、Gerry Rhodes、Luiz Belardinelli、Manoj C. Desai

  DOI：10.1021/acs.jmedchem.6b00939

  日期：2016.10.13

  Late sodium current (late I-Na) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na-v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-velitricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I-Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anterioior descending, LAD, occlusion in rabbits); with EC50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I-Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.