4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzonitrile | 1353884-73-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzonitrile
• 英文别名: 4-[5-[4-(4-piperazin-1-ylphenyl)-5-(2-pyrimidin-5-ylphenyl)-5H-1,2,4-oxadiazol-3-yl]furan-2-yl]benzonitrile
• CAS: 1353884-73-7
• 化学式: C₃₃H₂₇N₇O₂
• 分子量: 553.623
• InChiKey: ZLCHYXMKVDHWGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  42
• 可旋转键数：
  6
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzonitrile 在 CHIRALCEL OD 作用下， 以 乙醇 、 正己烷 、 二乙胺 为溶剂， 生成 4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzonitrile 、 4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzonitrile
  参考文献：
  名称：

  Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors

  摘要：

  Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.

  DOI：

  10.1021/ml200238g
• 作为产物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 4-(5-(4-(4-(piperazin-1-yl)phenyl)-5-(2-(pyrimidin-5-yl)phenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl)furan-2-yl)benzonitrile
  参考文献：
  名称：

  Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors

  摘要：

  Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.

  DOI：

  10.1021/ml200238g

文献信息

• Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors
  作者：Jun Qin、Pawan Dhondi、Xianhai Huang、Robert Aslanian、James Fossetta、Fang Tian、Daniel Lundell、Anandan Palani

  DOI：10.1021/ml200238g

  日期：2012.2.9

  Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.