(2R)-2-benzyl-3-[3-[[[4-(3,3-dimethylpiperidin-1-yl)benzoyl]amino]methyl]-4-propoxyphenyl]propanoic acid | 1622872-31-4

• 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: (2R)-2-benzyl-3-[3-[[[4-(3,3-dimethylpiperidin-1-yl)benzoyl]amino]methyl]-4-propoxyphenyl]propanoic acid
• CAS: 1622872-31-4
• 化学式: C₃₄H₄₂N₂O₄
• 分子量: 542.718
• InChiKey: APPIJDBGUOOXLM-MUUNZHRXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  40
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,2,2,4'-四氟苯乙酮 在 lithium hydroxide monohydrate 、 双氧水 、 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.5h， 生成 (2R)-2-benzyl-3-[3-[[[4-(3,3-dimethylpiperidin-1-yl)benzoyl]amino]methyl]-4-propoxyphenyl]propanoic acid
  参考文献：
  名称：

  Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists

  摘要：

  We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with 3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of α-benzylphenylpropanoic acid derivatives 8. As expected, most of the newly synthesized compounds exhibited more potent hPPARγ agonistic activity and greater hPPARγ binding affinity than 3. Some of these compounds also showed comparable aqueous solubility to 3.

  DOI：

  10.1016/j.bmcl.2014.06.023

文献信息

• Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists
  作者：Yuta Tanaka、Kanae Gamo、Takuji Oyama、Masao Ohashi、Minoru Waki、Kenji Matsuno、Nobuyasu Matsuura、Hiroaki Tokiwa、Hiroyuki Miyachi

  DOI：10.1016/j.bmcl.2014.06.023

  日期：2014.8

  We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with 3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined. Therefore, we constructed and inserted a plausible omega loop by means of molecular dynamics simulation. We then used the reconstructed LBD structure to design new mono-, bi- and tricyclic amine-bearing compounds that might be expected to show greater binding affinity for the LBD. Here, we describe synthesis and evaluation of α-benzylphenylpropanoic acid derivatives 8. As expected, most of the newly synthesized compounds exhibited more potent hPPARγ agonistic activity and greater hPPARγ binding affinity than 3. Some of these compounds also showed comparable aqueous solubility to 3.