(E)-2-(3-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile | 1421784-93-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噁庚英
• 英文名称: (E)-2-(3-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile
• 英文别名: (2E)-2-[3-fluoro-8-[(2-propylbenzimidazol-1-yl)methyl]-6H-benzo[c][1]benzoxepin-11-ylidene]propanenitrile
• CAS: 1421784-93-1
• 化学式: C₂₈H₂₄FN₃O
• 分子量: 437.516
• InChiKey: VGQDSGMENXFLFF-MTDXEUNCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  50.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (E)-2-(3-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile 在 羟胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 1.5h， 生成 (E)-3-(1-(3-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)ethyl)-1,2,4-oxadiazol-5(4H)-one
  参考文献：
  名称：

  Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

  摘要：

  We previously identified dibenzooxepine derivative 1 as a potent PPAR. ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPAR. activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-alpha]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

  DOI：

  10.1016/j.bmc.2019.115122
• 作为产物：
  描述：

  propyl 11-(1-cyanoethylidene)-3-fluoro-6,11-dihydrodibenzo[b,e]oxepin-8-carboxylate 在 2,6-二甲基吡啶 、 锂硼氢 、 potassium carbonate 、 lithium bromide 、 甲基磺酸酐 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 (E)-2-(3-fluoro-8-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile
  参考文献：
  名称：

  Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold

  摘要：

  We previously identified dibenzooxepine derivative 1 as a potent PPAR. ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPAR. activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-alpha]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.

  DOI：

  10.1016/j.bmc.2019.115122

文献信息

• DIBENZOOXEPIN DERIVATIVE
  申请人：Kyowa Hakko Kirin Co., Ltd.

  公开号：EP2740730B1

  公开（公告）日：2016-11-16
• US8969345B2
  申请人：——

  公开号：US8969345B2

  公开（公告）日：2015-03-03
• Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold
  作者：Keisuke Yamamoto、Tomohiro Tamura、Rina Nakamura、Shintaro Hosoe、Masahiro Matsubara、Keiko Nagata、Hiroshi Kodaira、Takeshi Uemori、Yuichi Takahashi、Michihiko Suzuki、Jun-ichi Saito、Kimihisa Ueno、Satoshi Shuto

  DOI：10.1016/j.bmc.2019.115122

  日期：2019.11

  We previously identified dibenzooxepine derivative 1 as a potent PPAR. ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPAR. activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-alpha]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPAR gamma ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.