1-(5-叔丁基-2-甲基吡唑-3-基)-3-(4-氯苯基)脲 | 432042-02-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 1-(5-叔丁基-2-甲基吡唑-3-基)-3-(4-氯苯基)脲
• 英文名称: 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-chlorophenyl)urea
• 英文别名: BI-1；1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(4-chlorophenyl)urea；RL8；1-(5-Tert-butyl-2-methyl-2H-pyrazol-3-YL)-3-(4-chloro-phenyl)-urea；1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-(4-chlorophenyl)urea
• CAS: 432042-02-9
• 化学式: C₁₅H₁₉ClN₄O
• 分子量: 306.795
• InChiKey: FWIJKWMXNHRSRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 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：

  对氯苯异氰酸酯 、 5-氨基-3-叔丁基-1-甲基吡唑 以 甲苯 为溶剂， 反应 24.0h， 以23%的产率得到1-(5-叔丁基-2-甲基吡唑-3-基)-3-(4-氯苯基)脲
  参考文献：
  名称：

  Development of a Fluorescent-Tagged Kinase Assay System for the Detection and Characterization of Allosteric Kinase Inhibitors

  摘要：

  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.

  DOI：

  10.1021/ja902010p

文献信息

• 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。
• 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。
• Advanced drug development and manufacturing
  申请人：Los Alamos National Security, LLC

  公开号：EP2511844A2

  公开（公告）日：2012-10-17

  There is described an apparatus for measuring protein characteristics comprising an X-ray fluorescence (XRF) spectrometer comprising a source of polychromatic X-rays, an X-ray detector, a protein, a molecule that has been exposed to and at least weakly binds to the protein, a plurality of X-ray fluorescence signal data obtained by irradiating chemical elements in the protein and molecule with the polychromatic X-rays and a security system for maintaining records for the data from the plurality of X-ray fluorescence signal measurements. There is also described an x-ray microscope for measuring a sample.

  描述了一种测量蛋白质特性的仪器，该仪器包括一个 X 射线荧光 (XRF) 光谱仪，其中包括一个多色 X 射线源、一个 X 射线探测器、一个蛋白质、一个已暴露于该蛋白质并至少与该蛋白质弱结合的分子、通过用多色 X 射线照射蛋白质和分子中的化学元素而获得的多个 X 射线荧光信号数据，以及一个用于维护多个 X 射线荧光信号测量数据记录的安全系统。此外，还介绍了一种用于测量样品的 X 射线显微镜。
• CRYSTALLOGRAPHIC STRUCTURE OF MNK-1 AND MNK-2 PROTEINS
  申请人：DeveloGen Aktiengesellschaft

  公开号：EP1856252A1

  公开（公告）日：2007-11-21
• ADVANCED DRUG DEVELOPMENT AND MANUFACTURING
  申请人：Los Alamos National Security, LLC

  公开号：EP2084519A2

  公开（公告）日：2009-08-05