(S)-methyl 2-(4-phenylphenoxy)-3-phenylpropanoate

• 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: (S)-methyl 2-(4-phenylphenoxy)-3-phenylpropanoate
• 英文别名: methyl (S)-2-(4-phenylphenoxy)-3-phenylpropanoate；methyl (2S)-3-phenyl-2-(4-phenylphenoxy)propanoate
• 化学式: C₂₂H₂₀O₃
• 分子量: 332.399
• InChiKey: FUZJSMWOZOKNNH-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-methyl 2-(4-phenylphenoxy)-3-phenylpropanoate 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 以76%的产率得到LT175
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling Investigation of New Chiral Fibrates with PPARα and PPARγ Agonist Activity

  摘要：

  Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyper-lipidemia (fibrates) and insulin resistance (glitazones). Thus, there is significant interest in developing new and specific ligands for these receptors. Here, we present the results of the screening of new ligands of PPAR alpha and PPAR gamma. Optical isomers of new chiral fibrates were synthesized and tested in cell-based assays. Compound (S)-7 showed a dual PPARU alpha/gamma activity, and its stereochemistry was crucial in receptor activation. Protease protection experiments suggested that this compound binds directly to PPAR. Moreover, computational studies showed that it properly docks to PPAR alpha and gamma ligand binding pockets. Interestingly, (S)-7 exhibited only a modest capacity to induce the differentiation of murine fibroblasts 3T3-L1 into adipocytes compared to rosiglitazone, a well-known PPAR gamma agonist.

  DOI：

  10.1021/jm0502844
• 作为产物：
  描述：

  对羟基联苯 、 D-苯基乳酸甲酯 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 甲苯 为溶剂， 以52%的产率得到(S)-methyl 2-(4-phenylphenoxy)-3-phenylpropanoate
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Molecular Modeling Investigation of New Chiral Fibrates with PPARα and PPARγ Agonist Activity

  摘要：

  Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyper-lipidemia (fibrates) and insulin resistance (glitazones). Thus, there is significant interest in developing new and specific ligands for these receptors. Here, we present the results of the screening of new ligands of PPAR alpha and PPAR gamma. Optical isomers of new chiral fibrates were synthesized and tested in cell-based assays. Compound (S)-7 showed a dual PPARU alpha/gamma activity, and its stereochemistry was crucial in receptor activation. Protease protection experiments suggested that this compound binds directly to PPAR. Moreover, computational studies showed that it properly docks to PPAR alpha and gamma ligand binding pockets. Interestingly, (S)-7 exhibited only a modest capacity to induce the differentiation of murine fibroblasts 3T3-L1 into adipocytes compared to rosiglitazone, a well-known PPAR gamma agonist.

  DOI：

  10.1021/jm0502844

文献信息

• Synthesis, Biological Evaluation, and Molecular Modeling Investigation of New Chiral Fibrates with PPARα and PPARγ Agonist Activity
  作者：Alessandra Pinelli、Cristina Godio、Antonio Laghezza、Nico Mitro、Giuseppe Fracchiolla、Vincenzo Tortorella、Antonio Lavecchia、Ettore Novellino、Jean-Charles Fruchart、Bart Staels、Maurizio Crestani、Fulvio Loiodice

  DOI：10.1021/jm0502844

  日期：2005.8.1

  Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular diseases, obesity, and diabetes. Medications targeted to PPARs have been established to treat hyper-lipidemia (fibrates) and insulin resistance (glitazones). Thus, there is significant interest in developing new and specific ligands for these receptors. Here, we present the results of the screening of new ligands of PPAR alpha and PPAR gamma. Optical isomers of new chiral fibrates were synthesized and tested in cell-based assays. Compound (S)-7 showed a dual PPARU alpha/gamma activity, and its stereochemistry was crucial in receptor activation. Protease protection experiments suggested that this compound binds directly to PPAR. Moreover, computational studies showed that it properly docks to PPAR alpha and gamma ligand binding pockets. Interestingly, (S)-7 exhibited only a modest capacity to induce the differentiation of murine fibroblasts 3T3-L1 into adipocytes compared to rosiglitazone, a well-known PPAR gamma agonist.
• Crystal Structure of the Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligand Binding Domain Complexed with a Novel Partial Agonist: A New Region of the Hydrophobic Pocket Could Be Exploited for Drug Design
  作者：Roberta Montanari、Fulvio Saccoccia、Elena Scotti、Maurizio Crestani、Cristina Godio、Federica Gilardi、Fulvio Loiodice、Giuseppe Fracchiolla、Antonio Laghezza、Paolo Tortorella、Antonio Lavecchia、Ettore Novellino、Fernando Mazza、Massimiliano Aschi、Giorgio Pochetti

  DOI：10.1021/jm800733h

  日期：2008.12.25

  The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPAR gamma, and provide an explanation on a molecular basis for their different potency and efficacy against PPAR gamma. The more potent S-enantionier is a dual PPAR alpha/PPAR gamma agonist which presents a partial agonism profile against PPAR gamma. Docking of the S-enantiomer in the PPAR alpha-LBD has been performed to explain its different Subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPAR gamma-LBD never sampled before by other ligands.