4'-chloro-2'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid

• 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: 4'-chloro-2'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
• 英文别名: 5-(4-Chloro-2-fluorophenyl)-2-hydroxybenzoic acid；5-(4-chloro-2-fluorophenyl)-2-hydroxybenzoic acid
• 化学式: C₁₃H₈ClFO₃
• 分子量: 266.656
• InChiKey: IAFBETLGGDHENG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  57.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4'-chloro-2'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid 在 bis(pyridine)iodonium tetrafluoroborate 作用下， 以 二氯甲烷 为溶剂， 生成 4'-chloro-2'-fluoro-4-hydroxy-5-iodo-[1,1'-biphenyl]-3-carboxylic acid
  参考文献：
  名称：

  Optimization of kinetic stabilizers of tetrameric transthyretin: A prospective ligand efficiency-guided approach

  摘要：

  In the past few years, attempts have been made to use decision criteria beyond Lipinski's guidelines (Rule of five) to guide drug discovery projects more effectively. Several variables and formulations have been proposed and investigated within the framework of multiparameter optimization methods to guide drug discovery. In this context, the combination of Ligand Efficiency Indices (LEI) has been predominantly used to map and monitor the drug discovery process in a retrospective fashion. Here we provide an example of the use of a novel application of the LEI methodology for prospective lead optimization by using the transthyretin (TTR) fibrillogenesis inhibitor iododiflunisal (IDIF) as example. Using this approach, a number of compounds with theoretical efficiencies higher than the reference compound IDIF were identified. From this group, ten compounds were selected, synthesized and biologically tested. Half of the compounds (5, 6, 7, 8 and 10) showed potencies in terms of IC50 inhibition of TTR aggregation equal or higher than the lead compound. These optimized compounds mapped within the region of more efficient candidates in the corresponding experimental nBEI-NSEI plot, matching their position in the theoretical optimization plane that was used for the prediction. Due to their upstream (North-Eastern) position in the progression lines of NPOL = 3 or 4 of the nBEI-NSEI plot, three of them (5, 6 and 8) are more interesting candidates than iododiflunisal because they have been optimized in the three crucial LEI variables of potency, size and polarity at the same time. This is the first example of the effectiveness of using the combined LEIs within the decision process to validate the application of the LEI formulation for the prospective optimization of lead compounds.

  DOI：

  10.1016/j.bmc.2020.115794
• 作为产物：
  描述：

  5-碘水杨酸 、 4-氯-2-氟苯硼酸 在 sodium carbonate 作用下， 以 水 为溶剂， 生成 4'-chloro-2'-fluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
  参考文献：
  名称：

  Optimization of kinetic stabilizers of tetrameric transthyretin: A prospective ligand efficiency-guided approach

  摘要：

  In the past few years, attempts have been made to use decision criteria beyond Lipinski's guidelines (Rule of five) to guide drug discovery projects more effectively. Several variables and formulations have been proposed and investigated within the framework of multiparameter optimization methods to guide drug discovery. In this context, the combination of Ligand Efficiency Indices (LEI) has been predominantly used to map and monitor the drug discovery process in a retrospective fashion. Here we provide an example of the use of a novel application of the LEI methodology for prospective lead optimization by using the transthyretin (TTR) fibrillogenesis inhibitor iododiflunisal (IDIF) as example. Using this approach, a number of compounds with theoretical efficiencies higher than the reference compound IDIF were identified. From this group, ten compounds were selected, synthesized and biologically tested. Half of the compounds (5, 6, 7, 8 and 10) showed potencies in terms of IC50 inhibition of TTR aggregation equal or higher than the lead compound. These optimized compounds mapped within the region of more efficient candidates in the corresponding experimental nBEI-NSEI plot, matching their position in the theoretical optimization plane that was used for the prediction. Due to their upstream (North-Eastern) position in the progression lines of NPOL = 3 or 4 of the nBEI-NSEI plot, three of them (5, 6 and 8) are more interesting candidates than iododiflunisal because they have been optimized in the three crucial LEI variables of potency, size and polarity at the same time. This is the first example of the effectiveness of using the combined LEIs within the decision process to validate the application of the LEI formulation for the prospective optimization of lead compounds.

  DOI：

  10.1016/j.bmc.2020.115794