4-[4-(2-chlorobenzyl)-4-methoxy-piperidin-1-yl]-benzoic acid ethyl ester | 926933-73-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-[4-(2-chlorobenzyl)-4-methoxy-piperidin-1-yl]-benzoic acid ethyl ester
• 英文别名: Ethyl 4-[4-[(2-chlorophenyl)methyl]-4-methoxypiperidin-1-yl]benzoate
• CAS: 926933-73-5
• 化学式: C₂₂H₂₆ClNO₃
• 分子量: 387.906
• InChiKey: WDRJGSCECMLUPJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[4-(2-chlorobenzyl)-4-methoxy-piperidin-1-yl]-benzoic acid ethyl ester 在 4-二甲氨基吡啶 、 lithium hydroxide 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 12.0h， 生成 4-{4-[(2-chlorophenyl)methyl]-4-methoxypiperidin-1-yl}-N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene)sulfonyl]benzamide
  参考文献：
  名称：

  Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

  摘要：

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

  DOI：

  10.1021/jm061152t
• 作为产物：
  描述：

  氯[(2-氯苯基)甲基]镁 在 sodium hydride 作用下， 以 四氢呋喃 、 乙醚 为溶剂， 反应 2.0h， 生成 4-[4-(2-chlorobenzyl)-4-methoxy-piperidin-1-yl]-benzoic acid ethyl ester
  参考文献：
  名称：

  Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

  摘要：

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

  DOI：

  10.1021/jm061152t

文献信息

• Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL
  作者：Milan Bruncko、Thorsten K. Oost、Barbara A. Belli、Hong Ding、Mary K. Joseph、Aaron Kunzer、Darlene Martineau、William J. McClellan、Michael Mitten、Shi-Chung Ng、Paul M. Nimmer、Tilman Oltersdorf、Cheol-Min Park、Andrew M. Petros、Alexander R. Shoemaker、Xiaohong Song、Xilu Wang、Michael D. Wendt、Haichao Zhang、Stephen W. Fesik、Saul H. Rosenberg、Steven W. Elmore

  DOI：10.1021/jm061152t

  日期：2007.2.1

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.