9-amino-5H-pyrrolo[2,1-α]isoindol-5-one | 322690-62-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 9-amino-5H-pyrrolo[2,1-α]isoindol-5-one
• 英文别名: 9-Aminopyrrolo[1,2-b]isoindol-5-one
• CAS: 322690-62-0
• 化学式: C₁₁H₈N₂O
• 分子量: 184.197
• InChiKey: SIUZWILXNPENDY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  48
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-异氰酸酯吡啶 、 9-amino-5H-pyrrolo[2,1-α]isoindol-5-one 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 1-(5-Oxopyrrolo[2,1-a]isoindol-9-yl)-3-pyridin-2-ylurea
  参考文献：
  名称：

  Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors:  New de Novo Design Strategy and Library Design

  摘要：

  As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC50 = 0.10 muM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC50 = 0.042 muM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.

  DOI：

  10.1021/jm0103256
• 作为产物：
  描述：

  2-溴-3-硝基苯甲酰氯 在 盐酸 、 四(三苯基膦)钯 、 potassium acetate 、 铁粉 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 反应 20.5h， 生成 9-amino-5H-pyrrolo[2,1-α]isoindol-5-one
  参考文献：
  名称：

  Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors:  New de Novo Design Strategy and Library Design

  摘要：

  As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC50 = 0.10 muM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC50 = 0.042 muM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.

  DOI：

  10.1021/jm0103256

文献信息

• Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors:  New <i>de Novo</i> Design Strategy and Library Design
  作者：Teruki Honma、Kyoko Hayashi、Tetsuya Aoyama、Noriaki Hashimoto、Takumitsu Machida、Kazuhiro Fukasawa、Toshiharu Iwama、Chinatsu Ikeura、Mari Ikuta、Ikuko Suzuki-Takahashi、Yoshikazu Iwasawa、Takashi Hayama、Susumu Nishimura、Hajime Morishima

  DOI：10.1021/jm0103256

  日期：2001.12.1

  As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC50 = 0.10 muM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC50 = 0.042 muM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.