9-(3-Methoxyphenyl)-4-methylsulfonyl-1,3,5,9,11-pentazatetracyclo[8.7.0.02,7.012,17]heptadeca-2,4,6,10,12,14,16-heptaen-8-one | 1015077-26-5

• 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: 9-(3-Methoxyphenyl)-4-methylsulfonyl-1,3,5,9,11-pentazatetracyclo[8.7.0.02,7.012,17]heptadeca-2,4,6,10,12,14,16-heptaen-8-one
• CAS: 1015077-26-5
• 化学式: C₂₀H₁₅N₅O₄S
• 分子量: 421.436
• InChiKey: YUEGZCBPMNDMCN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  116
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(4-甲基哌嗪)苯胺 、 9-(3-Methoxyphenyl)-4-methylsulfonyl-1,3,5,9,11-pentazatetracyclo[8.7.0.02,7.012,17]heptadeca-2,4,6,10,12,14,16-heptaen-8-one 以 异丙醇 为溶剂， 生成 6-(3-(methyloxy)phenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]-pyrimido[1,2-a]benzimidazol-5(6H)-one
  参考文献：
  名称：

  Structure-Based Design of Novel 2-Amino-6-phenyl-pyrimido[5′,4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as Potent and Orally Active Inhibitors of Lymphocyte Specific Kinase (Lck): Synthesis, SAR, and In Vivo Anti-Inflammatory Activity

  摘要：

  Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological, characterization of 2-amino-6phenylpyrirnido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.

  DOI：

  10.1021/jm701095m
• 作为产物：
  描述：

  9-(3-Methoxyphenyl)-4-methylsulfanyl-1,3,5,9,11-pentazatetracyclo[8.7.0.02,7.012,17]heptadeca-2,4,6,10,12,14,16-heptaen-8-one 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 20.0h， 生成 9-(3-Methoxyphenyl)-4-methylsulfonyl-1,3,5,9,11-pentazatetracyclo[8.7.0.02,7.012,17]heptadeca-2,4,6,10,12,14,16-heptaen-8-one
  参考文献：
  名称：

  Structure-Based Design of Novel 2-Amino-6-phenyl-pyrimido[5′,4′:5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as Potent and Orally Active Inhibitors of Lymphocyte Specific Kinase (Lck): Synthesis, SAR, and In Vivo Anti-Inflammatory Activity

  摘要：

  Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological, characterization of 2-amino-6phenylpyrirnido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.

  DOI：

  10.1021/jm701095m

文献信息

• Structure-Based Design of Novel 2-Amino-6-phenyl-pyrimido[5′,4′:5,6]pyrimido[1,2-<i>a</i>]benzimidazol-5(6<i>H</i>)-ones as Potent and Orally Active Inhibitors of Lymphocyte Specific Kinase (Lck): Synthesis, SAR, and In Vivo Anti-Inflammatory Activity
  作者：Matthew W. Martin、John Newcomb、Joseph J. Nunes、Christina Boucher、Lilly Chai、Linda F. Epstein、Theodore Faust、Sylvia Flores、Paul Gallant、Anu Gore、Yan Gu、Faye Hsieh、Xin Huang、Joseph L. Kim、Scot Middleton、Kurt Morgenstern、Antonio Oliveira-dos-Santos、Vinod F. Patel、David Powers、Paul Rose、Yanyan Tudor、Susan M. Turci、Andrew A. Welcher、Debra Zack、Huilin Zhao、Li Zhu、Xiaotian Zhu、Chiara Ghiron、Monika Ermann、David Johnston、Carl-Gustaf Pierre Saluste

  DOI：10.1021/jm701095m

  日期：2008.3.1

  Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological, characterization of 2-amino-6phenylpyrirnido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2-a]benzimidazol-5(6H)-one (25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.