(+)-(S)-[5'-chloro-1-(5-chloro-2-fluorobenzyl)-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid | 1262426-95-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (+)-(S)-[5'-chloro-1-(5-chloro-2-fluorobenzyl)-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid
• 英文别名: 2-[(4S)-5'-chloro-1-[(5-chloro-2-fluorophenyl)methyl]-2,2',5-trioxospiro[imidazolidine-4,3'-indole]-1'-yl]acetic acid
• CAS: 1262426-95-8
• 化学式: C₁₉H₁₂Cl₂FN₃O₅
• 分子量: 452.226
• InChiKey: HORZMXGVSURXCK-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (+)-(S)-[5'-chloro-1-(5-chloro-2-fluorobenzyl)-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid 在 potassium carbonate 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 [(+)-(S)-5'-chloro-1-(5-chloro-2-fluorobenzyl)-2,2',5-trioxo-3-propylspiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid
  参考文献：
  名称：

  Optimization of the Central Core of Indolinone–Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists

  摘要：

  New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC(50) = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%). This compound is also active in a mouse model of ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.

  DOI：

  10.1021/ml2001196
• 作为产物：
  描述：

  tert-butyl 2-(5'-chloro-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl)acetate 在 potassium carbonate 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.25h， 生成 (-)-(R)-[5'-chloro-1-(5-chloro-2-fluorobenzyl)-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid 、 (+)-(S)-[5'-chloro-1-(5-chloro-2-fluorobenzyl)-2,2',5-trioxospiro[imidazolidine-4,3'-indol]-1'(2'H)-yl]acetic acid
  参考文献：
  名称：

  Optimization of the Central Core of Indolinone–Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists

  摘要：

  New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC(50) = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%). This compound is also active in a mouse model of ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.

  DOI：

  10.1021/ml2001196

文献信息

• Optimization of the Central Core of Indolinone–Acetic Acid-Based CRTH2 (DP2) Receptor Antagonists
  作者：Stefano Crosignani、Catherine Jorand-Lebrun、Patrick Page、Gordon Campbell、Véronique Colovray、Marc Missotten、Yves Humbert、Christophe Cleva、Jean-François Arrighi、Marilène Gaudet、Zoe Johnson、Pamela Ferro、André Chollet

  DOI：10.1021/ml2001196

  日期：2011.8.11

  New spiroindolinone antagonists of CRTH2 are described. Following identification of insufficient stability in human plasma as an important liability of the lead compounds, replacement of the spirosuccinimide core with a spirohydantoin or spiropyrrolidinone structure has yielded a compound that is fully stable in human plasma and with good potency in a human whole blood assay (IC(50) = 69 nM) but shows a much lower oral bioavailability (6-9% in rodents) than the earlier compounds. Successive optimization aimed at restoring an acceptable oral bioavailability has yielded compound (S)-17a, which exhibits both stability in human plasma and a good oral bioavailability in rat (37%) and mouse (39%). This compound is also active in a mouse model of ovalbumin-induced lung inflammation following oral dosing at 30 mg/kg.