1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-chlorophenyl)urea | 852670-29-2

• 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-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-chlorophenyl)urea
• 英文别名: 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea；RL17；1-[5-Tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-(4-chlorophenyl)urea
• CAS: 852670-29-2
• 化学式: C₂₁H₂₃ClN₄O
• 分子量: 382.893
• InChiKey: SXYDUPCCSOBLBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  59
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  新戊酰基乙腈 、 对甲基苯肼 以 二氯甲烷 为溶剂， 生成 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-chlorophenyl)urea
  参考文献：
  名称：

  p38α激酶抑制剂多拉哌莫德及其类似物的生物物理研究和构象分析† ‡

  摘要：

  Doramapimod（BIRB 796）是p38α丝裂原活化蛋白激酶的有效抑制剂。它包含芳基-吡唑支架，作为对结合至关重要的药效基团。芳基-吡唑支架不是平面的并且采用平面外构型，其由扭转角θ描述。在这封信中，我们报告了doramapimod（3-12）的不同类似物的化学合成和生物物理特征，它们表现出明显不同的芳基-吡唑扭转角θ值。合成类似物的扭转角θ值（3–6）通过晶体结构分析确定，并通过微尺度热泳研究与p38α激酶的结合亲和力。我们的研究结果揭示了激酶结合与被测多拉吡莫德类似物的扭转角θ之间存在明显的相关性，突出了抑制剂构象对蛋白质结合的重要性。

  DOI：

  10.1039/c6md00262e

文献信息

• UREA DERIVATIVES AS ABL MODULATORS
  申请人：Grotzfeld Robert M.

  公开号：US20100173917A1

  公开（公告）日：2010-07-08

  The invention provides methods and compositions for treating conditions mediated by Bcr-Abl. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

  本发明提供了治疗由Bcr-Abl介导的疾病的方法和组合物。本发明还提供了使用这些化合物和/或组合物治疗受试者的各种疾病和不良情况的方法。
• Development of a Fluorescent-Tagged Kinase Assay System for the Detection and Characterization of Allosteric Kinase Inhibitors
  作者：Jeffrey R. Simard、Matthäus Getlik、Christian Grütter、Vijaykumar Pawar、Sabine Wulfert、Matthias Rabiller、Daniel Rauh

  DOI：10.1021/ja902010p

  日期：2009.9.23

  Kinase disregulation disrupts the intricate network of intracellular signaling pathways and contributes to the onset of diseases such as cancer. Although several kinase inhibitors are on the market, inhibitor selectivity and drug resistance mutations persist as fundamental challenges in the development of effective long-term treatments. Chemical entities binding to less conserved allosteric sites would be expected to offer new opportunities for scaffold development. Because no high-throughput method was previously available, we developed a fluorescence-based kinase binding assay for identifying and characterizing ligands which stabilize the inactive kinase conformation. Here, we present a description of the development and validation of this assay using the serine/threonine kinase p38alpha. By covalently attaching fluorophores to the activation loop of the kinase, we were able to detect conformational changes and measure the K(d), k(on), and k(off) associated with the binding and dissociation of ligands to the allosteric pocket. We report the SAR of a synthesized focused library of pyrazolourea derivatives, a scaffold known to bind with high affinity to the allosteric pocket of p38alpha. Additionally, we used protein X-ray crystallography together with our assay to examine the binding and dissociation kinetics to characterize potent quinazoline- and quinoline-based type II inhibitors, which also utilize this binding pocket in p38alpha. Last, we identified the b-Raf inhibitor sorafenib as a potent low nanomolar inhibitor of p38alpha and used protein X-ray crystallography to confirm a unique binding mode to the inactive kinase conformation.
• 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.
• US7750160B2
  申请人：——

  公开号：US7750160B2

  公开（公告）日：2010-07-06
• Biophysical investigation and conformational analysis of p38α kinase inhibitor doramapimod and its analogues
  作者：Amir H. Nasiri、Krishna Saxena、Jan W. Bats、Hamid R. Nasiri、Harald Schwalbe

  DOI：10.1039/c6md00262e

  日期：——

  angle θ values of the synthesized analogues (3–6) were determined by crystal structural analysis and the binding affinities to p38α kinase investigated by microscale thermophoresis. Our results unveil a clear correlation between kinase binding and the torsion angle θ of tested doramapimod analogues, highlighting the importance of inhibitor conformation for protein binding.

  Doramapimod（BIRB 796）是p38α丝裂原活化蛋白激酶的有效抑制剂。它包含芳基-吡唑支架，作为对结合至关重要的药效基团。芳基-吡唑支架不是平面的并且采用平面外构型，其由扭转角θ描述。在这封信中，我们报告了doramapimod（3-12）的不同类似物的化学合成和生物物理特征，它们表现出明显不同的芳基-吡唑扭转角θ值。合成类似物的扭转角θ值（3–6）通过晶体结构分析确定，并通过微尺度热泳研究与p38α激酶的结合亲和力。我们的研究结果揭示了激酶结合与被测多拉吡莫德类似物的扭转角θ之间存在明显的相关性，突出了抑制剂构象对蛋白质结合的重要性。