i-butyl 4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate | 1408382-23-9

• 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: i-butyl 4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
• 英文别名: 2-Methylpropyl 2,7,7-trimethyl-5-oxo-4-(4-phenylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate；2-methylpropyl 2,7,7-trimethyl-5-oxo-4-(4-phenylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate
• CAS: 1408382-23-9
• 化学式: C₂₉H₃₃NO₃
• 分子量: 443.586
• InChiKey: WYHUPOLWGOCERL-UHFFFAOYSA-N

物化性质

• 沸点：
  585.4±50.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  对苯基苯甲醛 在 ammonium acetate 、 碘 、 三氯化硼 、 potassium carbonate 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 i-butyl 4-(biphenyl-4-yl)-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

• Synthesis and SAR of <i>b</i>-Annulated 1,4-Dihydropyridines Define Cardiomyogenic Compounds as Novel Inhibitors of TGFβ Signaling
  作者：Dennis Schade、Marion Lanier、Erik Willems、Karl Okolotowicz、Paul Bushway、Christine Wahlquist、Cynthia Gilley、Mark Mercola、John R. Cashman

  DOI：10.1021/jm301144g

  日期：2012.11.26

  A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor beta (TGF beta)/Smad signaling by clearing the type II TGF beta receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGF beta inhibition, and evaluated SAR aspects for cell-surface clearance of TGF beta receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGF beta inhibition in the nanomolar range (e.g., compound. 28, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGF beta inhibition for the (+)- than the (-) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.
• 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.