(2S,3R)-methyl 2-(3-nitrobenzamido)-3-(3-oxobutanoyloxy)-butanoate | 1394961-61-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S,3R)-methyl 2-(3-nitrobenzamido)-3-(3-oxobutanoyloxy)-butanoate
• 英文别名: methyl (2S,3R)-2-(3-nitrobenzamido)-3-(3-oxobutanoyloxy)butanoate；methyl (2S,3R)-2-[(3-nitrobenzoyl)amino]-3-(3-oxobutanoyloxy)butanoate
• CAS: 1394961-61-5
• 化学式: C₁₆H₁₈N₂O₈
• 分子量: 366.328
• InChiKey: PZYFSPVNDLHVGT-YGRLFVJLSA-N

物化性质

• 沸点：
  512.3±50.0 °C(predicted)
• 密度：
  1.315±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  26
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  145
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2S,3R)-methyl 2-(3-nitrobenzamido)-3-(3-oxobutanoyloxy)-butanoate 、 5-丙基-1,3-环己烷二酮 、 对苯基苯甲醛 在 ammonium acetate 、 碘 作用下， 以 乙醇 为溶剂， 反应 20.0h， 生成 methyl (2S,3R)-3-{[2-methyl-5-oxo-4-(4-phenylphenyl)-7-propyl-1,4,5,6,7,8-hexahydroquinolin-3-yl]carbonyloxy}-2-[(3-nitrophenyl)formamido]butanoate
  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
• 作为产物：
  描述：

  双乙烯酮 、 (2S,3R)-methyl 3-hydroxy-2-(3-nitrobenzamido)butanoate 在 4-二甲氨基吡啶 作用下， 以 四氢呋喃 为溶剂， 以78%的产率得到(2S,3R)-methyl 2-(3-nitrobenzamido)-3-(3-oxobutanoyloxy)-butanoate
  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

• 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.
• 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.