ethyl 4-(4-(4-pyridyl)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: ethyl 4-(4-(4-pyridyl)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
• 英文别名: Ethyl 2,7,7-trimethyl-5-oxo-4-(4-pyridin-4-ylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate；ethyl 2,7,7-trimethyl-5-oxo-4-(4-pyridin-4-ylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate
• 化学式: C₂₆H₂₈N₂O₃
• 分子量: 416.52
• InChiKey: XQVLEAQELYAORD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  68.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  乙酰乙酸乙酯 在 四(三苯基膦)钯 、 ammonium acetate 、 碘 、 sodium carbonate 作用下， 以 乙醇 、 水 、 异丙醇 为溶剂， 反应 0.17h， 生成 ethyl 4-(4-(4-pyridyl)phenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
  参考文献：
  名称：

  Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors

  摘要：

  Targeting TGF beta/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. through induction of TGF beta receptor type II degradation. In the present work, >40 rationally designed, novel DHPs were synthesized and evaluated for TGF beta inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4"-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are (R)configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r(2) = 0.93) with a good predictive power (r(pred)(2) = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGF beta inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands (e.g., lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies in vivo. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.03.027

文献信息

• Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors
  作者：Daniel Längle、Viktoria Marquardt、Elena Heider、Brigita Vigante、Gunars Duburs、Iveta Luntena、Dirk Flötgen、Christopher Golz、Carsten Strohmann、Oliver Koch、Dennis Schade

  DOI：10.1016/j.ejmech.2015.03.027

  日期：2015.5

  Targeting TGF beta/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. through induction of TGF beta receptor type II degradation. In the present work, >40 rationally designed, novel DHPs were synthesized and evaluated for TGF beta inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4"-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are (R)configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r(2) = 0.93) with a good predictive power (r(pred)(2) = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGF beta inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands (e.g., lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies in vivo. (C) 2015 Elsevier Masson SAS. All rights reserved.