N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-(4-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-1H-1,2,3-triazol-1-yl)acetamide) | 1614229-00-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-(4-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-1H-1,2,3-triazol-1-yl)acetamide)
• 英文别名: N-(3-Cyclopropyl-1-Phenyl-1h-Pyrazol-5-Yl)-2-{4-[3-Methoxy-4-(4-Methyl-1h-Imidazol-1-Yl)phenyl]-1h-1,2,3-Triazol-1-Yl}acetamide；N-(5-cyclopropyl-2-phenylpyrazol-3-yl)-2-[4-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]triazol-1-yl]acetamide
• CAS: 1614229-00-3
• 化学式: C₂₇H₂₆N₈O₂
• 分子量: 494.556
• InChiKey: FQGDIYVVDKJSNC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-环丙基-1-苯基-1H-吡唑-5-胺 在 sodium azide 、 铜 、 copper(II) sulfate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 、 叔丁醇 为溶剂， 反应 17.0h， 生成 N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-(4-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-1H-1,2,3-triazol-1-yl)acetamide)
  参考文献：
  名称：

  Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain

  摘要：

  We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

  DOI：

  10.1021/jm5006429

文献信息

• Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain
  作者：Shawn J. Stachel、John M. Sanders、Darrell A. Henze、Mike T. Rudd、Hua-Poo Su、Yiwei Li、Kausik K. Nanda、Melissa S. Egbertson、Peter J. Manley、Kristen L. G. Jones、Edward J. Brnardic、Ahren Green、Jay A. Grobler、Barbara Hanney、Michael Leitl、Ming-Tain Lai、Vandna Munshi、Dennis Murphy、Keith Rickert、Daniel Riley、Alicja Krasowska-Zoladek、Christopher Daley、Paul Zuck、Stephanie A. Kane、Mark T. Bilodeau

  DOI：10.1021/jm5006429

  日期：2014.7.10

  We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.