4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid | 1408382-80-8

• 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: 4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid
• 英文别名: 2,7,7-Trimethyl-5-oxo-4-(4-phenylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylic acid；2,7,7-trimethyl-5-oxo-4-(4-phenylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylic acid
• CAS: 1408382-80-8
• 化学式: C₂₅H₂₅NO₃
• 分子量: 387.478
• InChiKey: MDWGQNDXBJQGLJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  66.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid 在 氨 、 potassium carbonate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 45.0h， 生成 (3-methyl-3H-diazirin-3-yl)methyl 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：

  独特的光亲和探针可研究TGFβ信号传导和受体命运†

  摘要：

  一种新颖的合成方法用于制备带有光亲和性标记的多种不同的“同类”的基于二氢吡啶的TGFβ受体降解剂。这些探针可作为研究TGFβ受体命运和动力学的宝贵工具，这是化学生物学中的一项重要挑战。

  DOI：

  10.1039/c9cc00929a
• 作为产物：
  描述：

  methyl 4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 在 三氯化硼 作用下， 以 二氯甲烷 为溶剂， 以75%的产率得到4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid
  参考文献：
  名称：

  Synthesis and SAR of b-Annulated 1,4-Dihydropyridines Define Cardiomyogenic Compounds as Novel Inhibitors of TGFβ Signaling

  摘要：

  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.

  DOI：

  10.1021/jm301144g

文献信息

• Toward Second-Generation Cardiomyogenic and Anti-cardiofibrotic 1,4-Dihydropyridine-Class TGFβ Inhibitors
  作者：Daniel Längle、Tessa R. Werner、Fabian Wesseler、Elena Reckzeh、Niklas Schaumann、Lauren Drowley、Magnus Polla、Alleyn T. Plowright、Marc N. Hirt、Thomas Eschenhagen、Dennis Schade

  DOI：10.1002/cmdc.201900036

  日期：2019.4.17

  Innovative therapeutic modalities for pharmacological intervention of transforming growth factor β (TGFβ)-dependent diseases are of great value. b-Annelated 1,4-dihydropyridines (DHPs) might be such a class, as they induce TGFβ receptor type II degradation. However, intrinsic drawbacks are associated with this compound class and were systematically addressed in the presented study. It was possible

  药物治疗转化生长因子β（TGFβ）依赖性疾病的创新治疗方式具有重要价值。b-带环的1,4-二氢吡啶（DHP）可能属于此类，因为它们会诱导II型TGFβ受体降解。但是，固有的缺点与此化合物类相关联，并在本研究中系统地解决了。可以在分子的不同部位安装极性官能团和生物立体异构部分，同时保持TGFβ抑制活性。引入2-氨基或7-N-烷基修饰被证明是成功的策略。相对于母体乙基4-（联苯基-4-基）-2,7,7-三甲基-5-氧代-1,4，在pH 7.4时，水溶解度最多可提高7倍，在pH 3时可提高200倍。 ，5,6,7,8-六氢喹啉-3-羧酸盐。
• 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.
• Unique photoaffinity probes to study TGFβ signaling and receptor fates
  作者：D. Längle、F. Wesseler、D. Flötgen、H. Leek、A. T. Plowright、D. Schade

  DOI：10.1039/c9cc00929a

  日期：——

  A novel synthetic approach is used to prepare a diverse set of “first-in-class” dihydropyridine-based TGFβ receptor degraders bearing photoaffinity labels. These probes serve as valuable tools to study TGFβ receptor fates and dynamics – an important challenge in chemical biology.

  一种新颖的合成方法用于制备带有光亲和性标记的多种不同的“同类”的基于二氢吡啶的TGFβ受体降解剂。这些探针可作为研究TGFβ受体命运和动力学的宝贵工具，这是化学生物学中的一项重要挑战。
• 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.