tert-butyl (6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:5,4-c′]dipyridin-3-yl)carbamate | 1200130-60-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: tert-butyl (6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:5,4-c′]dipyridin-3-yl)carbamate
• 英文别名: 3-tert-butoxycarbonylamino-9-(2-trimethylsilanylethoxymethyl)dipyrido[2,3-b:4',3'-d]pyrrole-6-carbonitrile；tert-butyl N-[4-cyano-8-(2-trimethylsilylethoxymethyl)-5,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]carbamate
• CAS: 1200130-60-4
• 化学式: C₂₂H₂₉N₅O₃Si
• 分子量: 439.589
• InChiKey: JFAMTLFSEDCHRN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.12
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl (6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:5,4-c′]dipyridin-3-yl)carbamate 在 硫酸 、 三氟乙酸 、 sodium nitrite 作用下， 以 二氯甲烷 、 水 、 溶剂黄146 为溶剂， 反应 60.33h， 生成 3-chloro-9-(2-trimethylsilanylethoxymethyl)dipyrido[2,3-b:4',3'-d]pyrrole-6-carbonitrile
  参考文献：
  名称：

  [EN] DIAZACARBAZOLES AND METHODS OF USE
  [FR] DIAZACARBAZOLES ET PROCÉDÉS D'UTILISATION

  摘要：

  公开号：

  WO2009151598A8
• 作为产物：
  描述：

  3-bromo-9H-pyrrolo[2,3-b:5,4-c′]dipyridine-6-carboxamide 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸酐 、 sodium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.5h， 生成 tert-butyl (6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:5,4-c′]dipyridin-3-yl)carbamate
  参考文献：
  名称：

  Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

  摘要：

  Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

  DOI：

  10.1021/acs.jmedchem.5b00464

文献信息

• [EN] DIAZACARBAZOLES AND METHODS OF USE<br/>[FR] DIAZACARBAZOLES ET PROCÉDÉS D'UTILISATION
  申请人：GENENTECH INC

  公开号：WO2009151598A8

  公开（公告）日：2010-05-06
• Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1
  作者：Lewis Gazzard、Karen Williams、Huifen Chen、Lorraine Axford、Elizabeth Blackwood、Brenda Burton、Kerry Chapman、Peter Crackett、Joy Drobnick、Charles Ellwood、Jennifer Epler、Michael Flagella、Emanuela Gancia、Matthew Gill、Simon Goodacre、Jason Halladay、Joanne Hewitt、Hazel Hunt、Samuel Kintz、Joseph Lyssikatos、Calum Macleod、Sarah Major、Guillaume Médard、Raman Narukulla、Judi Ramiscal、Stephen Schmidt、Eileen Seward、Christian Wiesmann、Ping Wu、Sharon Yee、Ivana Yen、Shiva Malek

  DOI：10.1021/acs.jmedchem.5b00464

  日期：2015.6.25

  Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.