8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid 2-(morpholin-4-yl)ethyl amide | 1417403-99-6

• 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: 8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid 2-(morpholin-4-yl)ethyl amide
• 英文别名: 8-chloro-N-(2-morpholinethyl)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide；8-chloro-N-(2-morpholinoethyl)-5-oxo-10,11-dihydro-5H-dibenzo[a,d][7]annulene-3-carboxamide；13-chloro-N-(2-morpholin-4-ylethyl)-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide
• CAS: 1417403-99-6
• 化学式: C₂₂H₂₃ClN₂O₃
• 分子量: 398.889
• InChiKey: BARSEVATJIGQFI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid 2-(morpholin-4-yl)ethyl amide 在 草酰氯 、 [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1‘-biphenyl)-2-(2‘-amino-1,1’-biphenyl)]palladium(II) methanesulfonate 、 potassium carbonate 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 N-(2-fluoro-5-((7-((2-morpholinoethyl)carbamoyl)-5-oxo-10,11-dihydro-5hdibenzo[a,d][7]annulen-2-yl)amino)phenyl)selenophene-2-carboxamide
  参考文献：
  名称：

  N-酰基hydr和硒烯的芳族酰胺连接的脊柱残基的生物立体置换作为一种设计策略，以新颖的二苯并亚砜衍生物作为I 1/2p38αMAP激酶抑制剂。

  摘要：

  p38αMAPK的I 1/2型抑制剂的最新披露表明，如何将R脊柱的稳定化用作增加抑制剂的目标停留时间（TRT）的策略。在本文中，我们首次将N-酰基and和硒基残基描述为脊柱基序，产生了对酶，NanoBRET和全血检测具有高效效的代谢稳定抑制剂，改善了代谢稳定性，并延长了TRT。

  DOI：

  10.1021/acs.jmedchem.0c00508
• 作为产物：
  描述：

  4-甲基-异酞腈 在 aluminum (III) chloride 、 正丁基锂 、 氯化亚砜 、 硫酸 、 水 、 二异丙胺 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 二氯甲烷 、 二乙二醇 为溶剂， 反应 134.83h， 生成 8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-3-carboxylic acid 2-(morpholin-4-yl)ethyl amide
  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

• Design, Synthesis, and Biological Evaluation of Novel Type I¹/₂ p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine
  作者：Niklas M. Walter、Heike K. Wentsch、Mike Bührmann、Silke M. Bauer、Eva Döring、Svenja Mayer-Wrangowski、Adrian Sievers-Engler、Nicole Willemsen-Seegers、Guido Zaman、Rogier Buijsman、Michael Lämmerhofer、Daniel Rauh、Stefan A. Laufer

  DOI：10.1021/acs.jmedchem.7b00745

  日期：2017.10.12

  We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine

  我们最近报告了1a（skepinone-L）作为I型p38αMAP激酶抑制剂，在体外和体内均具有很高的效价和出色的选择性。但是，作为I型抑制剂，它完全具有ATP竞争能力，并且仅显示适度的停留时间。因此，研究范围是开发一种新型的高级化合物，该化合物可维持skepinone-L支架的结构结合特征，例如在铰链区诱导甘氨酸翻转，并同时占据疏水区I和II。用适当的残基扩展该支架会干扰激酶的R-Spine。通过合成69种化合物，我们可以将一个实例的目标停留时间显着延长至3663 s，同时具有出色的选择性得分0.006和出色的效能1.0 nM。通过共结晶验证了这种新的结合模式，1 / 2的结合。此外，微粒体研究显示了最有效的，本文报道的代表的便利的代谢稳定性。
• 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.
• Bioisosteric Replacement of Arylamide-Linked Spine Residues with <i>N</i>-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type I 1/2 p38α MAP Kinase Inhibitors
  作者：Júlia G. B. Pedreira、Philipp Nahidino、Mark Kudolo、Tatu Pantsar、Benedict-Tilman Berger、Michael Forster、Stefan Knapp、Stefan Laufer、Eliezer J. Barreiro

  DOI：10.1021/acs.jmedchem.0c00508

  日期：2020.7.9

  The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe N-acylhydrazone and selenophene residues as spine motifs, yielding metabolically stable inhibitors with high potency on enzymatic, NanoBRET, and whole blood

  p38αMAPK的I 1/2型抑制剂的最新披露表明，如何将R脊柱的稳定化用作增加抑制剂的目标停留时间（TRT）的策略。在本文中，我们首次将N-酰基and和硒基残基描述为脊柱基序，产生了对酶，NanoBRET和全血检测具有高效效的代谢稳定抑制剂，改善了代谢稳定性，并延长了TRT。