5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile | 946150-87-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile
• 英文别名: 5-Amino-1-(2-hydroxy-2-phenylethyl)pyrazole-4-carbonitrile
• CAS: 946150-87-4
• 化学式: C₁₂H₁₂N₄O
• 分子量: 228.253
• InChiKey: PDXSBZMISZODAX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  87.9
• 氢给体数：
  2
• 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-carbonitrile 在 sodium ethanolate 、 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 1-(2-hydroxy-2-phenylethyl)-6-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
  参考文献：
  名称：

  作为 Src 抑制剂的吡唑并[3,4-d]嘧啶衍生物 SI388 的鉴定和生物学表征

  摘要：

  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。

  DOI：

  10.3390/ph16070958
• 作为产物：
  描述：

  氧化苯乙烯 在 hydrazine hydrate 作用下， 以 乙醇 为溶剂， 反应 6.25h， 生成 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carbonitrile
  参考文献：
  名称：

  Design, synthesis and biological evaluation of new pyrazolyl-ureas and imidazopyrazolecarboxamides able to interfere with MAPK and PI3K upstream signaling involved in the angiogenesis

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2017.03.066

文献信息

• Synthesis and Biological Evaluation of <i>N</i>-Pyrazolyl-<i>N</i>‘-alkyl/benzyl/phenylureas:  a New Class of Potent Inhibitors of Interleukin 8-Induced Neutrophil Chemotaxis
  作者：Olga Bruno、Chiara Brullo、Francesco Bondavalli、Silvia Schenone、Angelo Ranise、Nicoletta Arduino、Maria B. Bertolotto、Fabrizio Montecucco、Luciano Ottonello、Franco Dallegri、Massimiliano Tognolini、Vigilio Ballabeni、Simona Bertoni、Elisabetta Barocelli

  DOI：10.1021/jm0704402

  日期：2007.7.1

  Neutrophils chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation and a number of autoimmune diseases. We report here the synthesis of a new N-(4-substituted)pyrazolyl-N'-alkyl/benzyl/phenylureas that are potent inhibitors of interleukin-8 (IL8)-induced neutrophil chemotaxis. The first series of compounds, obtained by functionalization with a urea moiety of the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3, blocked the IL8-induced neutrophil chemotaxis, while they did not block N-formylmethionylleucylphenylalanine-mediated chemotaxis. The most active compounds, 3-benzyl- (4d), 3-(4-benzylpiperazinyl)- (4i), 3-phenyl- (4k) and 3-isopropylureido (4a) derivatives, showed an IC50 of 10, 14, 45, and 55 nM, respectively. Several different molecules were then synthesized to obtain more information for SAR study. Compounds 4a, 4d, and 4k were inactive in the binding assays on CXCR1 and CXCR2 (IL8 receptors), whereas they inhibited the phosphorylation of PTKs (protein tyrosine kinases) in the 50-70 kDa region. Moreover, in the presence of the same derivatives, we observed a complete block of F-actin rise and pseudopod formation.
• 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.
• 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
  作者：Cristina Tintori、Giuseppina La Sala、Giulia Vignaroli、Lorenzo Botta、Anna Lucia Fallacara、Federico Falchi、Marco Radi、Claudio Zamperini、Elena Dreassi、Lucia Dello Iacono、Donata Orioli、Giuseppe Biamonti、Mirko Garbelli、Andrea Lossani、Francesca Gasparrini、Tiziano Tuccinardi、Ilaria Laurenzana、Adriano Angelucci、Giovanni Maga、Silvia Schenone、Chiara Brullo、Francesca Musumeci、Andrea Desogus、Emmanuele Crespan、Maurizio Botta

  DOI：10.1021/acs.jmedchem.5b00140

  日期：2015.6.11

  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.
• Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines
  作者：Silvia Schenone、Chiara Brullo、Olga Bruno、Francesco Bondavalli、Luisa Mosti、Giovanni Maga、Emmanuele Crespan、Fabio Carraro、Fabrizio Manetti、Cristina Tintori、Maurizio Botta

  DOI：10.1016/j.ejmech.2008.01.034

  日期：2008.12

  The synthesis of new 4-amino substituted pyrazolo[3,4-d]pyrimidines along with their activity in cell-free enzymatic assays on Src and Abl tyrosine kinases is reported. Some compounds emerged as good dual inhibitors of the two enzymes, showed antiproliferative effects on two Bcr-Abl positive leukemia cell lines K-562 and KU-812, and induced apoptosis, as demonstrated by the PARP assay. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction with both Src and Abl. (C) 2008 Elsevier Masson SAS. All rights reserved.
• 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
  作者：Chiara Brullo、Susanna Spisani、Rita Selvatici、Olga Bruno

  DOI：10.1016/j.ejmech.2011.11.031

  日期：2012.1

  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.