methyl (+/-)-4-(5-(1-cyclopropylpiperidin-4-yloxy)-1H-benzo[d]imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzoate | 1276687-69-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: methyl (+/-)-4-(5-(1-cyclopropylpiperidin-4-yloxy)-1H-benzo[d]imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzoate
• 英文别名: Methyl 4-[5-(1-cyclopropylpiperidin-4-yl)oxybenzimidazol-1-yl]-2-[1-[2-(trifluoromethyl)phenyl]ethoxy]benzoate
• CAS: 1276687-69-4
• 化学式: C₃₂H₃₂F₃N₃O₄
• 分子量: 579.619
• InChiKey: CEEXXXNNHCTEGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  42
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  65.8
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl (+/-)-4-(5-(1-cyclopropylpiperidin-4-yloxy)-1H-benzo[d]imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzoate 在 氨 作用下， 以 甲醇 为溶剂， 反应 120.0h， 以32%的产率得到(+/-)-4-(5-(1-cyclopropylpiperidin-4-yloxy)-1H-benzo[d]imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzamide
  参考文献：
  名称：

  Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure−Activity Relationship

  摘要：

  We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.

  DOI：

  10.1021/jm1011726
• 作为产物：
  描述：

  methyl (+/-)-4-(5-hydroxy-1H-benzo[d]imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzoate 在 偶氮二甲酸二叔丁酯 、 sodium cyanoborohydride 、 溶剂黄146 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 methyl (+/-)-4-(5-(1-cyclopropylpiperidin-4-yloxy)-1H-benzo[d]imidazol-1-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethoxy)benzoate
  参考文献：
  名称：

  Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure−Activity Relationship

  摘要：

  We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.

  DOI：

  10.1021/jm1011726

文献信息

• Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure−Activity Relationship
  作者：Savade Solanki、Paolo Innocenti、Corine Mas-Droux、Kathy Boxall、Caterina Barillari、Rob L. M. van Montfort、G. Wynne Aherne、Richard Bayliss、Swen Hoelder

  DOI：10.1021/jm1011726

  日期：2011.3.24

  We describe herein the structure-activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.