ethyl 5-amino-1-(2-phenylpropyl)-1H-pyrazole-4-carboxylate | 1283727-52-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 5-amino-1-(2-phenylpropyl)-1H-pyrazole-4-carboxylate
• CAS: 1283727-52-5
• 化学式: C₁₅H₁₉N₃O₂
• 分子量: 273.335
• InChiKey: VGNZJTMBFFSPLD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.45
• 重原子数：
  20.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  70.14
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  ethyl 5-amino-1-(2-phenylpropyl)-1H-pyrazole-4-carboxylate 在 N,N-二甲基甲酰胺 、 三氯氧磷 作用下， 以 氯仿 为溶剂， 反应 13.0h， 生成 4-chloro-1-(2-phenylpropyl)-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-d]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study

  摘要：

  A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.

  DOI：

  10.1021/jm1012819
• 作为产物：
  描述：

  (2-溴丙基)苯 在 肼 作用下， 以 乙醇 为溶剂， 反应 29.0h， 生成 ethyl 5-amino-1-(2-phenylpropyl)-1H-pyrazole-4-carboxylate
  参考文献：
  名称：

  Design, Synthesis, Biological Activity, and ADME Properties of Pyrazolo[3,4-d]pyrimidines Active in Hypoxic Human Leukemia Cells: A Lead Optimization Study

  摘要：

  A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported by us and proved to be active against several tumor cell lines. Among these compounds, a promising antileukemia lead (1) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead 1 is described in the present work. A series of more soluble pyrazolo[3,4-d]pyrimidine derivatives were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compounds showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water solubility, microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogues of lead 1 as promising antileukemia agents.

  DOI：

  10.1021/jm1012819

文献信息

• Novel pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl kinase inhibitors: Synthesis and biological evaluation for chronic myeloid leukemia treatment
  作者：Salvatore Di Maria、Francesca Picarazzi、Mattia Mori、Annarita Cianciusi、Anna Carbone、Emmanuele Crespan、Cecilia Perini、Samantha Sabetta、Serenella Deplano、Federica Poggialini、Alessio Molinari、Rossella Aronne、Elias Maccioni、Giovanni Maga、Adriano Angelucci、Silvia Schenone、Francesca Musumeci、Elena Dreassi

  DOI：10.1016/j.bioorg.2022.106071

  日期：2022.11

  molecules active as dual Src/Bcr-Abl inhibitors emerged as effective targeted therapies for CML and a few compounds are currently in clinical use. In this study, we applied a target-oriented approach to identify a family of pyrazolo[3,4-d]pyrimidines as dual Src/Bcr-Abl inhibitors as anti-leukemia agents. Considering the high homology between Src and Bcr-Abl, in-house Src inhibitors 8a-l and new analogue compounds

  Bcr-Abl 酪氨酸激酶 (TK) 是慢性粒细胞白血病 (CML) 的分子标志。Src 是另一种 TK 激酶，其参与 CML 已被广泛证实。作为双 Src/Bcr-Abl 抑制剂活性的小分子作为 CML 的有效靶向疗法出现，一些化合物目前正在临床使用。在这项研究中，我们应用了一种靶向方法来确定吡唑并[3,4- d ]嘧啶家族作为双 Src/Bcr-Abl 抑制剂作为抗白血病药物。考虑到 Src 和 Bcr-Abl 之间的高度同源性，内部Src 抑制剂8a-l和新的类似化合物9a-n被筛选为双重 Src/Bcr-Abl 抑制剂。确定了最有希望的化合物对 K562 CML 细胞的抗增殖活性和 ADME 谱。分子模型研究阐明了抑制剂与 Bcr-Abl (wt) 催化口袋的结合模式。化合物8j和8k在酶促和细胞测定中显示出纳摩尔活性，以及​​良好的 ADME 特性，成为 CML 治疗的有希望的候
• Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells
  作者：Marco Radi、Chiara Brullo、Emmanuele Crespan、Cristina Tintori、Francesca Musumeci、Mariangela Biava、Silvia Schenone、Elena Dreassi、Claudio Zamperini、Giovanni Maga、Dafne Pagano、Adriano Angelucci、Mauro Bologna、Maurizio Botta

  DOI：10.1016/j.bmcl.2011.07.079

  日期：2011.10

  Neuroblastoma (NB) represents the most common extracranial paediatric solid tumor for which no specific FDA-approved treatment is currently available. The tyrosine kinase c-Src has been reported to play an important role in the differentiation, cell-adhesion and survival of NB cells. Starting from dual Src/Abl inhibitors previously found active in NB cell lines (1-3), small modification of the original structures almost abolished the Abl activity with a contemporary improvement of affinity and specificity for cSrc. Among the synthesized compounds, the most potent c-Src inhibitor (10a) showed a very interesting antiproliferative activity in SH-SY5Y cells with an IC50 of 80 nM and a favourable ADME profile. A 3D SAR analysis was also attempted and may guide the design of more potent c-Src inhibitors as potential agents for NB treatment. (C) 2011 Elsevier Ltd. All rights reserved.