3-(6-(methylthio)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenol | 1583284-81-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 3-(6-(methylthio)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenol
• 英文别名: 3-[[6-Methylsulfanyl-1-(2-phenylethyl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]phenol；3-[[6-methylsulfanyl-1-(2-phenylethyl)pyrazolo[3,4-d]pyrimidin-4-yl]amino]phenol
• CAS: 1583284-81-4
• 化学式: C₂₀H₁₉N₅OS
• 分子量: 377.47
• InChiKey: UVACNPSFJYZFME-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-(methylthio)-1-(2-phenylethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]-pyrimidin-4-one 在 三氯氧磷 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 3-(6-(methylthio)-1-phenethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenol
  参考文献：
  名称：

  Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma

  摘要：

  c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.

  DOI：

  10.1021/jm5013159

文献信息

• Exploring the Chemical Space around the Privileged Pyrazolo[3,4-<i>d</i>]pyrimidine Scaffold: Toward Novel Allosteric Inhibitors of T315I-Mutated Abl
  作者：Giulia Vignaroli、Martina Mencarelli、Deborah Sementa、Emmanuele Crespan、Miroslava Kissova、Giovanni Maga、Silvia Schenone、Marco Radi、Maurizio Botta

  DOI：10.1021/co500004e

  日期：2014.4.14

  screening of this “privileged scaffold”-based compound collection, validated the use of a diversity-oriented approach in a field characteristically explored by target-oriented synthesis. In fact, several compounds showed high activity against the selected kinases (i.e., Src, Abl wt, and T315I mutated-form), furthermore and interestingly a new compound has emerged as an allosteric inhibitor of the T315I mutated-form

  具有高水平分子多样性的吡唑并[3,4- d ]嘧啶文库已通过应用允许C3，N1，C4和C6取代的合成序列开发而成。对这种基于“特权支架”的化合物集合的酶促筛选，证实了在以目标为导向的合成为特征的领域中，以多样性为导向的方法的使用。实际上，几种化合物对选定的激酶表现出高活性（即Src，Abl wt和T315I突变形式），而且有趣的是，新化合物作为A315的T315I突变形式的变构抑制剂出现了，打开了大门。开发新型非竞争性Abl抑制剂（T315I）的新机会。
• COMPOUNDS AND USES THEREOF
  申请人：LEAD DISCOVERY SIENA S.R.L.

  公开号：US20180186796A1

  公开（公告）日：2018-07-05

  The present invention refers to 4-amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivatives of formula I and IV able to target the Src family kinases (SFKs) such as Src, Fyn and Hck tyrosine kinases as well as Abl tyrosine kinase and uses and method of preparation thereof. In particular, the compounds of the invention are for use in the treatment and/or prevention of cancer, such as neuroblastoma (NB) or glioblastoma multiforme (GBM) or for use in the treatment and/or prevention of neurodegenerative diseases such as taupathies.
• [EN] COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS ET LEURS UTILISATIONS
  申请人：LEAD DISCOVERY SIENA S R L

  公开号：WO2016066755A2

  公开（公告）日：2016-05-06

  The present invention refers to 4-amino-substituted pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine derivatives of formula I and IV able to target the Src family kinases (SFKs) such as Src, Fyn and Hck tyrosine kinases as well as Abl tyrosine kinase and uses and method of preparation thereof. In particular, the compounds of the invention are for use in the treatment and/or prevention of cancer, such as neuroblastoma (NB) or glioblastoma multiforme (GBM) or for use in the treatment and/or prevention of neurodegenerative diseases such as taupathies.
• Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-<i>d</i>]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma
  作者：Cristina Tintori、Anna Lucia Fallacara、Marco Radi、Claudio Zamperini、Elena Dreassi、Emmanuele Crespan、Giovanni Maga、Silvia Schenone、Francesca Musumeci、Chiara Brullo、André Richters、Francesca Gasparrini、Adriano Angelucci、Claudio Festuccia、Simona Delle Monache、Daniel Rauh、Maurizio Botta

  DOI：10.1021/jm5013159

  日期：2015.1.8

  c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.