1-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea | 1160934-70-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea
• 英文别名: 1-[1-(3-Aminophenyl)-3-Tert-Butyl-1h-Pyrazol-5-Yl]-3-Naphthalen-1-Ylurea；1-[2-(3-aminophenyl)-5-tert-butylpyrazol-3-yl]-3-naphthalen-1-ylurea
• CAS: 1160934-70-2
• 化学式: C₂₄H₂₅N₅O
• 分子量: 399.495
• InChiKey: HJWMLCDGRWWLAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  85
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea 、 溴乙酸甲酯 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以78%的产率得到methyl 2-(3-(3-tert-butyl-5-(3-naphthalen-1-ylureido)-1H-pyrazol-1-yl)phenylamino)acetate
  参考文献：
  名称：

  Displacement Assay for the Detection of Stabilizers of Inactive Kinase Conformations

  摘要：

  Targeting protein kinases with small molecules outside the highly conserved ATP pocket to stabilize inactive kinase conformati oils is becoming a more desirable approach in kinase inhibitor research, since these molecules have advanced pharmacological properties compared to compounds exclusively targeting the ATP pocket. Traditional screening approaches for kinase inhibitors arc often based on enzyme activity, but they may miss inhibitors that stabilize inactive kinase conformations by enriching the active state of the kinase. Here we present the development of a kinase binding assay employing a pyraZOIOUrea type III inhibitor and enzyme fragment complementation (EFQ technology that is suitable to screen stabilizers ofenzyniatically inactive kinases. To validate this assay system, we report tile binding characteristics of a series of kinase inhibitors to inactive p38(x and JNK2. Additionally, we present protein X-ray crystallography studies to examine the binding modes of potent quinolinc-based DFG-out binders in p38a.

  DOI：

  10.1021/jm901297e
• 作为产物：
  描述：

  1-(3-tert-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea 在 palladium on activated charcoal 、 甲酸铵 作用下， 以 乙醇 为溶剂， 反应 3.0h， 以44%的产率得到1-(1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl)urea
  参考文献：
  名称：

  Hybrid Compound Design To Overcome the Gatekeeper T338M Mutation in cSrc

  摘要：

  The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.

  DOI：

  10.1021/jm9002928

文献信息

• Fluorescently Or Spin-Labeled Kinases For Rapid Screening And Identification Of Novel Kinase Inhibitor Scaffolds
  申请人：Rauh Daniel

  公开号：US20110212475A1

  公开（公告）日：2011-09-01

  The present invention relates to a kinase labeled at an amino acid having a free thiol or amino group, wherein said amino acid is naturally present or introduced in the activation loop of said kinase, with (a) a thiol- or amino-reactive fluorophore sensitive to polarity changes in its environment; or (b) a thiol-reactive spin label, an isotope or an isotope-enriched thiol- or amino-reactive label, such that said fluorophore, spin label, isotope or isotope-enriched label does not inhibit the catalytic activity and does not interfere with the stability of the kinase. The invention furthermore relates to a method of screening for kinase inhibitor, a method of determining the kinetics of ligand binding and/or of dissociation of a kinase inhibitor and a method of generating mutated kinases suitable for the screening of kinase inhibitors using the kinase of the present invention.
• REGULATED BIOCIRCUIT SYSTEMS
  申请人：Obsidian Therapeutics, Inc.

  公开号：US20190192691A1

  公开（公告）日：2019-06-27

  The present invention provides regulatable biocircuit systems. Such systems provide modular and tunable protein expression systems in support of the discovery and development of therapeutic modalities.
• IDENTIFICATION AND TARGETED MODULATION OF GENE SIGNALING NETWORKS
  申请人：CAMP4 THERAPEUTICS CORPORATION

  公开号：US20210254056A1

  公开（公告）日：2021-08-19

  The present invention provides methods and compositions for the evaluation, alteration and/or optimization of gene signaling. Methods and systems are also provided which exploit the information generated in the identification of new targets and non-canonical signaling pathways.
• Hybrid Compound Design To Overcome the Gatekeeper T338M Mutation in cSrc
  作者：Matthäus Getlik、Christian Grütter、Jeffrey R. Simard、Sabine Klüter、Matthias Rabiller、Haridas B. Rode、Armin Robubi、Daniel Rauh

  DOI：10.1021/jm9002928

  日期：2009.7.9

  The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.
• Displacement Assay for the Detection of Stabilizers of Inactive Kinase Conformations
  作者：Sabine Klüter、Christian Grütter、Tabassum Naqvi、Matthias Rabiller、Jeffrey R. Simard、Vijaykumar Pawar、Matthäus Getlik、Daniel Rauh

  DOI：10.1021/jm901297e

  日期：2010.1.14

  Targeting protein kinases with small molecules outside the highly conserved ATP pocket to stabilize inactive kinase conformati oils is becoming a more desirable approach in kinase inhibitor research, since these molecules have advanced pharmacological properties compared to compounds exclusively targeting the ATP pocket. Traditional screening approaches for kinase inhibitors arc often based on enzyme activity, but they may miss inhibitors that stabilize inactive kinase conformations by enriching the active state of the kinase. Here we present the development of a kinase binding assay employing a pyraZOIOUrea type III inhibitor and enzyme fragment complementation (EFQ technology that is suitable to screen stabilizers ofenzyniatically inactive kinases. To validate this assay system, we report tile binding characteristics of a series of kinase inhibitors to inactive p38(x and JNK2. Additionally, we present protein X-ray crystallography studies to examine the binding modes of potent quinolinc-based DFG-out binders in p38a.