methyl 4-(biphenyl-4-yl)-2-ethyl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate | 1349689-29-7

• 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: methyl 4-(biphenyl-4-yl)-2-ethyl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
• 英文别名: Methyl 2-ethyl-7,7-dimethyl-5-oxo-4-(4-phenylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate；methyl 2-ethyl-7,7-dimethyl-5-oxo-4-(4-phenylphenyl)-1,4,6,8-tetrahydroquinoline-3-carboxylate
• CAS: 1349689-29-7
• 化学式: C₂₇H₂₉NO₃
• 分子量: 415.532
• InChiKey: TZWXTJBGMJZAMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 4-(biphenyl-4-yl)-2-ethyl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 在 silica gel 、 过碘酸 、 sodium nitrite 作用下， 以 二氯甲烷 为溶剂， 生成 methyl 4-(biphenyl-4-yl)-2-ethyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate
  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：

  3-氧代戊酸甲酯 、 5,5-二甲基-1,3-环己二酮 、 对苯基苯甲醛 在 ammonium acetate 、 碘 作用下， 以 乙醇 为溶剂， 生成 methyl 4-(biphenyl-4-yl)-2-ethyl-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
  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

• 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.