dimethyl (8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carbonyl)-L-glutamate | 1417404-44-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 二苯并环庚烯
• 英文名称: dimethyl (8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carbonyl)-L-glutamate
• 英文别名: dimethyl (2S)-2-[[13-(2,4-difluoroanilino)-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carbonyl]amino]pentanedioate
• CAS: 1417404-44-4
• 化学式: C₂₉H₂₆F₂N₂O₆
• 分子量: 536.532
• InChiKey: STTSHEDSPVREJI-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  39
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  dimethyl (8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carbonyl)-L-glutamate 在 甲醇 、 potassium hydroxide 作用下， 以66%的产率得到(8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carbonyl)-L-glutamic acid
  参考文献：
  名称：

  高选择性脑渗透p38α丝裂原活化蛋白激酶抑制剂的设计与合成

  摘要：

  应激诱导的 p38α 丝裂原活化蛋白 (MAP) 激酶激活调节细胞因子过度产生，并与神经炎症和神经变性有关。作为一种潜在的治疗方法，基于 Skepinone 的新型 p38α MAP 激酶抑制剂经过优化，可通过氨基酸转运蛋白或疏水扩散穿过血脑屏障。为了增强口服途径的吸收，我们使用了活性羧基类似物的甲酯前药。其中，3-(8-((2,4-二氟苯基)氨基)-5-oxo-10,11-dihydro- 5H - dibenzo[ a , d ][7]annulene-3-carboxamido)propanoic acid ( 43 ; p38α, IC 50 = 5.5 nM) 和 4-(8-((2,4-二氟苯基)氨基)-5-oxo-10,11-dihydro-5 H -dibenzo[a , d ][7] annulene-3-carboxamido)butanoic acid ( 44 ; p38α

  DOI：

  10.1021/acs.jmedchem.0c01773
• 作为产物：
  描述：

  4-甲基-异酞腈 在 盐酸 、 aluminum (III) chloride 、 正丁基锂 、 氯化亚砜 、 硫酸 、 potassium tert-butylate 、 水 、 palladium diacetate 、 三乙胺 、 二异丙胺 、 potassium hydroxide 、 sodium hydroxide 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 甲苯 、 叔丁醇 、 二乙二醇 为溶剂， 反应 143.33h， 生成 dimethyl (8-((2,4-difluorophenyl)amino)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carbonyl)-L-glutamate
  参考文献：
  名称：

  Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity

  摘要：

  p38 alpha mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38 alpha MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.

  DOI：

  10.1021/jm301539x

文献信息

• [EN] CENTRALLY ACTIVE P38ALPHA INHIBITING COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE P38ALPHA À ACTIVITÉ CENTRALE
  申请人：SYNOVO GMBH

  公开号：WO2021038292A1

  公开（公告）日：2021-03-04

  Compounds that are inhibitors of p38alpha and centrally available are described.

  描述了能够抑制p38alpha并且在中枢可用的化合物。
• Design and Synthesis of Highly Selective Brain Penetrant p38α Mitogen-Activated Protein Kinase Inhibitors
  作者：Niklas M. Tormählen、Mariella Martorelli、Annette Kuhn、Florian Maier、Jamil Guezguez、Michael Burnet、Wolfgang Albrecht、Stefan A. Laufer、Pierre Koch

  DOI：10.1021/acs.jmedchem.0c01773

  日期：2022.1.27

  Stress-induced p38α mitogen-activated protein (MAP) kinase activation modulates cytokine overproduction and is associated with neuroinflammation and neurodegeneration. As a potential therapeutic approach, novel Skepinone-based p38α MAP kinase inhibitors were optimized to cross the blood–brain barrier via either amino acid transporters or hydrophobic diffusion. To enhance absorption from the oral route

  应激诱导的 p38α 丝裂原活化蛋白 (MAP) 激酶激活调节细胞因子过度产生，并与神经炎症和神经变性有关。作为一种潜在的治疗方法，基于 Skepinone 的新型 p38α MAP 激酶抑制剂经过优化，可通过氨基酸转运蛋白或疏水扩散穿过血脑屏障。为了增强口服途径的吸收，我们使用了活性羧基类似物的甲酯前药。其中，3-(8-((2,4-二氟苯基)氨基)-5-oxo-10,11-dihydro- 5H - dibenzo[ a , d ][7]annulene-3-carboxamido)propanoic acid ( 43 ; p38α, IC 50 = 5.5 nM) 和 4-(8-((2,4-二氟苯基)氨基)-5-oxo-10,11-dihydro-5 H -dibenzo[a , d ][7] annulene-3-carboxamido)butanoic acid ( 44 ; p38α
• Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity
  作者：Stefan Fischer、Heike K. Wentsch、Svenja C. Mayer-Wrangowski、Markus Zimmermann、Silke M. Bauer、Kirsten Storch、Raimund Niess、Solveigh C. Koeberle、Christian Grütter、Frank M. Boeckler、Daniel Rauh、Stefan A. Laufer

  DOI：10.1021/jm301539x

  日期：2013.1.10

  p38 alpha mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38 alpha MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.