N-(cyanomethyl)-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(cyanomethyl)-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide
• 英文别名: US10344025, Example 527；N-(cyanomethyl)-1-[4-[6-[[2-[3-(trifluoromethoxy)phenyl]acetyl]amino]pyridazin-3-yl]butyl]triazole-4-carboxamide
• 化学式: C₂₂H₂₁F₃N₈O₃
• 分子量: 502.456
• InChiKey: GBEBRCDTKPPWHA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  148
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  methyl 1-(4-(6-aminopyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxylate 在 1-丙基磷酸酐 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 9.0h， 生成 N-(cyanomethyl)-1-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1H-1,2,3-triazole-4-carboxamide
  参考文献：
  名称：

  Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties

  摘要：

  Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

  DOI：

  10.1021/acs.jmedchem.0c01398

文献信息

• GLS1 INHIBITORS FOR TREATING DISEASE
  申请人：Board of Regents, The University of Texas System

  公开号：US20160009704A1

  公开（公告）日：2016-01-14

  Disclosed herein are compounds and compositions useful in the treatment of GLS1 mediated diseases, such as cancer, having the structure of Formula I: Methods of inhibition GLS1 activity in a human or animal subject are also provided.

  本文揭示了一些化合物和组合物，其结构公式为I，可用于治疗GLS1介导的疾病，如癌症。还提供了抑制人类或动物主体中GLS1活性的方法。
• HETEROCYCLIC GLS1 INHIBITORS
  申请人：Board of Regents, The University of Texas System

  公开号：EP3677579A1

  公开（公告）日：2020-07-08

  Disclosed herein are compounds and compositions useful in the treatment of GLS I mediated diseases, such as cancer, having the structure of Formula I. Methods of inhibition GLS I activity in a human or animal subject are also provided.

  本文公开了用于治疗 GLS I 介导的疾病（如癌症）的具有式 I 结构的化合物和组合物。还提供了抑制人或动物体内 GLS I 活性的方法。
• GLS1 inhibitors for treating disease
  申请人：Board of Regents, The University of Texas System

  公开号：US10344025B2

  公开（公告）日：2019-07-09

  Disclosed herein are compounds and compositions useful in the treatment of GLS1 mediated diseases, such as cancer, having the structure of Formula I: Methods of inhibition GLS1 activity in a human or animal subject are also provided.

  本文公开了用于治疗 GLS1 介导的疾病（如癌症）的化合物和组合物，其结构如式 I 所示： 还提供了抑制人或动物体内 GLS1 活性的方法。
• Glutaminase inhibitor therapy
  申请人：Board of Regents, The University of Texas System

  公开号：US10722487B2

  公开（公告）日：2020-07-28

  Disclosed herein are methods of treating a tumor or cancer in a subject whose tumor or cancer cells express low levels of asparagine synthetase (ASNS), and compounds and compositions useful in such treatment. Also disclosed herein are methods of evaluating whether to administer a compound that inhibits glutathione production or a glutaminase inhibitor to a subject with a tumor or cancer.

  本文公开了对肿瘤或癌细胞表达低水平天冬酰胺合成酶（ASNS）的受试者进行肿瘤或癌症治疗的方法，以及用于此类治疗的化合物和组合物。本文还公开了评估是否对肿瘤或癌症患者施用抑制谷胱甘肽生成的化合物或谷氨酰胺酶抑制剂的方法。
• GLS1 INHIBITORS FOR TREATING DISEASES
  申请人：Board of Regents, The University of Texas System

  公开号：EP3164394B1

  公开（公告）日：2020-04-01