ethyl 2-(3-chloro-4-formylphenoxy)-2-methylpropanoate | 1415228-44-2

• 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: ethyl 2-(3-chloro-4-formylphenoxy)-2-methylpropanoate
• CAS: 1415228-44-2
• 化学式: C₁₃H₁₅ClO₄
• 分子量: 270.713
• InChiKey: RLFXEBPJHLYRQJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(2-furanylmethyl)-5-methyl-2-phenyl-4-oxazolemethanamine 、 ethyl 2-(3-chloro-4-formylphenoxy)-2-methylpropanoate 在 sodium triacetoxyborohydride 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 2-[3-Chloro-4-[[furan-2-ylmethyl-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]amino]methyl]phenoxy]-2-methylpropanoic acid
  参考文献：
  名称：

  Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1)

  摘要：

  We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) alpha/gamma dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR alpha/gamma dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR alpha/gamma dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR alpha/gamma dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.092
• 作为产物：
  描述：

  2-溴-2-甲基丙酸乙酯 、 2-氯-4-羟基苯甲醛 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl 2-(3-chloro-4-formylphenoxy)-2-methylpropanoate
  参考文献：
  名称：

  Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1)

  摘要：

  We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) alpha/gamma dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR alpha/gamma dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR alpha/gamma dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR alpha/gamma dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.092

文献信息

• Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1)
  作者：Yoshihiro Shibata、Katsuji Kagechika、Mitsuhiro Yamaguchi、Hideo Kubo、Hiroyuki Usui

  DOI：10.1016/j.bmcl.2012.09.092

  日期：2012.12

  We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) alpha/gamma dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR alpha/gamma dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR alpha/gamma dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR alpha/gamma dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model. (C) 2012 Elsevier Ltd. All rights reserved.
• Discovery of novel allosteric site and covalent inhibitors of FBPase with potent hypoglycemic effects
  作者：Yunyuan Huang、Lin Wei、Xinya Han、Haifeng Chen、Yanliang Ren、Yanhong Xu、Rongrong Song、Li Rao、Chen Su、Chao Peng、Lingling Feng、Jian Wan

  DOI：10.1016/j.ejmech.2019.111749

  日期：2019.12

  Fructose-1,6-bisphosphatase (FBPase) is an essential enzyme of GNG pathway. Significant advances demonstrate the FBPase plays a critical role in treatment of diabetes. Numerous FBPase inhibitors were developed by targeting AMP site, nevertheless, none of these inhibitors has exhibited suitable potency and druggability. Herein, a new allosteric site (C128) on FBPase was discovered, and several nitrostyrene compounds exhibiting potent FBPase inhibitions were found covalently bind to C128 site on FBPase. Mutagenesis suggest that C128 is the only cysteine that can influence FBPase inhibition, the N125-S124-S123 pathway was most likely involved in allosteric signaling transmission between C128 and active site. However, these nitrostyrenes may bind with multiple cysteine besides C128 in FBPase. To improve pocket selectivity, a series of novel compounds (14a-14n) were re-designed rationally by integrating fragment-based covalent virtual screening and machine-learning-based synthetic complexity evaluation. As expected, the mass spectrometry validated that the proportion of title compounds binding to the C128 in FBPase was significantly higher than that of nitrostyrenes. Notably, under physiological and pathological conditions, the treatment of compounds 14b, 14c, 14i or 14n led to potent inhibition of glucose production, as well as decreased triglyceride and total cholesterol levels in mouse primary hepatocytes. We highlight a novel paradigm that molecular targeting C128 site on FBPase can have potent hypoglycemic effect. (C) 2019 Elsevier Masson SAS. All rights reserved.