1-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)amino)-4-methylphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea | 1033769-28-6

• 物质功能分类: 生物化工 - 抑制剂 - 蛋白酪氨酸激酶
• 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: 1-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)amino)-4-methylphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
• 英文别名: GNF5837；pan-Trk inhibitor；GNF 5837；GNF-5837；1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-methyl-3-[[2-oxo-3-(1H-pyrrol-2-ylmethylidene)-1H-indol-6-yl]amino]phenyl]urea
• CAS: 1033769-28-6
• 化学式: C₂₈H₂₁F₄N₅O₂
• 分子量: 535.501
• InChiKey: YYDUWLSETXNJJT-UHFFFAOYSA-N

物化性质

• 熔点：
  >228°C (dec.)
• 沸点：
  616.0±55.0 °C(Predicted)
• 密度：
  1.497±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶5mg/mL，澄清（加热）

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  98
• 氢给体数：
  5
• 氢受体数：
  7

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S36/37/39
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

GNF-5837是一种选择性的、口服生物有效的泛TRK抑制剂，对TrkA和TrkB的IC50值分别为12 nM和8 nM。

体外研究

在过表达具有持续活性的Tel-TRKC融合蛋白的Ba/F3细胞中，GNF-5837表现出有效的抗Trk活性和抗增殖活性，IC50为0.042 μM。

体内研究

在雄性Balb/c小鼠和Sprague–Dawley大鼠体内，GNF-5837具有低药物清除率和适度生物利用率。负荷Rie异种移植物表达TrkA 和 NGF的小鼠体内，口服给药（100 毫克/千克/天）显著抑制肿瘤生长。

靶点

TRK 型别	IC50 (nM)
TrkB	9 nM
TrkC	7 nM
TrkA	11 nM

反应信息

• 作为产物：
  描述：

  2-硝基-4-溴苯乙酸 在 哌啶 、 硫酸 、 palladium 10% on activated carbon 、 氢气 、 palladium diacetate 、 caesium carbonate 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 溶剂黄146 为溶剂， 反应 2.0h， 生成 1-(3-((3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-6-yl)amino)-4-methylphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
  参考文献：
  名称：

  Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

  摘要：

  Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.

  DOI：

  10.1021/ml200261d

文献信息

• Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models
  作者：Pam Albaugh、Yi Fan、Yuan Mi、Fangxian Sun、Francisco Adrian、Nanxin Li、Yong Jia、Yelena Sarkisova、Andreas Kreusch、Tami Hood、Min Lu、Guoxun Liu、Shenlin Huang、Zuosheng Liu、Jon Loren、Tove Tuntland、Donald S. Karanewsky、H. Martin Seidel、Valentina Molteni

  DOI：10.1021/ml200261d

  日期：2012.2.9

  Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.