5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide | 946150-88-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide
• 英文别名: 5-Amino-1-(2-hydroxy-2-phenylethyl)pyrazole-4-carboxamide
• CAS: 946150-88-5
• 化学式: C₁₂H₁₄N₄O₂
• 分子量: 246.269
• InChiKey: HXYQJRLOQGYIJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide 在 sodium ethanolate 、 三氯氧磷 作用下， 以 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 6-benzyl-4-chloro-1-(2-chloro-2-phenylethyl)-1H-pyrazolo-[3,4-d]pyrimidine
  参考文献：
  名称：

  Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors

  摘要：

  Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies,; such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K-i of about 2 mu M, while derivative 4a, derived from our internal library, showed a K-i of 0.9 mu M. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 44 having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of : the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.

  DOI：

  10.1021/acs.jmedchem.5b00140
• 作为产物：
  描述：

  2-hydrazino-1-phenylethanol 在 sodium hydroxide 作用下， 以 乙醇 、 水 为溶剂， 反应 8.0h， 生成 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxamide
  参考文献：
  名称：

  N-Aryl-2-phenyl-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted strongly inhibiting both fMLP-OMe- and IL-8-induced human neutrophil chemotaxis

  摘要：

  Anomalous activation of neutrophil recruitment is one of the causes of many inflammatory diseases. The chemoattractants N-formyl-methionyl-leucyl-phenylalanine (fMLP), and interleukine 8 (IL8) play a pivotal role in neutrophil chemotaxis regulation in the latter and early stages, respectively, probably by two independent mechanisms. We reported here synthesis and biological evaluation of new N-aryl-2-pheny1-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted which were designed as possible multi-target antiinflammatory agents. Many of the title compounds showed a good inhibition, in the nano molar range, of human neutrophil chemotaxis selectively acting toward fMLP-OMe (methylester of fMLP) or IL8 stimulus; whereas, two compounds showed an interesting dual activity inhibiting both fMLP-OMe and IL8-induced chemotaxis at nano molar concentration. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.11.031

文献信息

• Identification and Biological Characterization of the Pyrazolo[3,4-d]pyrimidine Derivative SI388 Active as Src Inhibitor
  作者：Claudia Contadini、Claudia Cirotti、Anna Carbone、Mehrdad Norouzi、Annarita Cianciusi、Emmanuele Crespan、Cecilia Perini、Giovanni Maga、Daniela Barilà、Francesca Musumeci、Silvia Schenone

  DOI：10.3390/ph16070958

  日期：——

  including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388)

  Src 是一种非受体酪氨酸激酶 (TK)，其与癌症（包括胶质母细胞瘤 (GBM)）的参与已被广泛证明。在这种情况下，我们从具有 Src 和/或 Bcr-Abl TK 抑制剂活性的吡唑并[3,4-d]嘧啶的内部库开始，进行了先导化合物优化研究，以发现适合的新一代衍生物用于 Src 激酶靶向。我们合成了 19 种化合物（2a-s）的库。其中，化合物 2a (SI388) 被确定为最有效的 Src 抑制剂。基于无细胞结果，我们研究了 SI388 在 2D 和 3D GBM 细胞模型中的作用。有趣的是，SI388 显着抑制 Src 激酶，从而影响细胞活力、致瘤性并增强癌细胞对电离辐射的敏感性。
• Design, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angiogenesis
  作者：Elda Meta、Chiara Brullo、Adama Sidibe、Beat A. Imhof、Olga Bruno

  DOI：10.1016/j.ejmech.2017.03.066

  日期：2017.6

  Taking into account the structure activity relationship information given by our previous studies, we designed and synthesized a small library of pyrazolylureas and imidazopyrazolecarboxamides fluorinated on urea moiety and differently decorated on pyrazole nucleus. All compounds were preliminary screened by Western blotting technique to evaluate their activity on MAPK and PI3K pathways by monitoring ERK1/2, p38MAPK and Akt phosphorylation, and also screened with a wound healing assay to assess their capacity in inhibiting endothelial cell migration, using human umbilical vein endothelial cells stimulated with VEGF. Pyrazoles and imidazopyrazoles did not show the same activity profile. SAR consideration showed that specific substituents and their position in pyrazole nucleus, as well as the type of substituent on the phenylurea moiety play a pivotal role in determining increase or decrease of kinases phosphorylation. On the other hand the loss of flexibility in imidazopyrazole derivatives is responsible for activity potentiation. Screening of the compound library for inhibition of endothelial cell migration, a function required for angiogenesis, showed significant activity for compound 3. This compound might interfere with cell migration by modulating the activity of different upstream target kinases. Therefore, compound 3 represents a potential inhibitor of angiogenesis. Furthermore, it may be used as a tool to identify unknown mediators of endothelial migration and thereby unveiling new therapeutic targets for controlling pathological angiogenesis in diseases such as cancers. (C) 2017 Elsevier Masson SAS. All rights reserved.
• 2-Phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives: New potent inhibitors of fMLP-induced neutrophil chemotaxis
  作者：Olga Bruno、Chiara Brullo、Francesco Bondavalli、Angelo Ranise、Silvia Schenone、Maria Sofia Falzarano、Katia Varani、Susanna Spisani

  DOI：10.1016/j.bmcl.2007.04.036

  日期：2007.7

  It is well known that both acute and chronic autoimmune inflammatory disorders arise following a breakdown in control of neutrophil activation and recruitment. In the search for new anti-inflammatory agents, we synthesized some new 2-phenyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives and tested them in vitro in order to evaluate their ability to interfere with human neutrophil functions. All tested compounds showed strong inhibition of fMLP-OMe-induced chemotaxis, although they appeared unable to block degranulation and the fMLP-OMe-induced respiratory burst, and were inactive in binding experiments. (c) 2007 Elsevier Ltd. All rights reserved.
• COMPOUNDS AND USES THEREOF
  申请人：Lead Discovery Siena S.r.l.

  公开号：EP3212649A2

  公开（公告）日：2017-09-06
• [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.