5-fluoro-2-{2-[(4aS,5S)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-7-oxo-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide | 1352240-48-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-fluoro-2-{2-[(4aS,5S)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-7-oxo-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide
• CAS: 1352240-48-2
• 化学式: C₂₆H₂₃F₂N₃O₃
• 分子量: 463.484
• InChiKey: MUNSXCDIXDYUOS-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.53
• 重原子数：
  34.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  98.21
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  5-fluoro-2-{2-[(4aS,5S)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-7-oxo-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide 在 sodium tetrahydroborate 、 乙醇 作用下， 反应 1.0h， 以41%的产率得到5-fluoro-2-{2-[(4aS,5S,7R)-1-(4-fluorophenyl)-5,7-dihydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide
  参考文献：
  名称：

  Discovery of selective glucocorticoid receptor modulator MK-5932

  摘要：

  A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.054
• 作为产物：
  描述：

  5-fluoro-2-{2-[(4aS,5S,7S)-1-(4-fluorophenyl)-5,7-dihydroxy-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide 在 戴斯-马丁氧化剂 、 碳酸氢钠 、 sodium thiosulfate 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 0.67h， 以94%的产率得到5-fluoro-2-{2-[(4aS,5S)-1-(4-fluorophenyl)-5-hydroxy-4a-methyl-7-oxo-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-yl]ethyl}benzamide
  参考文献：
  名称：

  Discovery of selective glucocorticoid receptor modulator MK-5932

  摘要：

  A series of partial agonists of the Glucocorticoid Receptor were prepared targeting reduced transactivation activity, while maintaining significant transrepression activity. Incorporation of an ortho-aryl amide produced compounds with the desired in vitro profile. Bioreactors consisting of Suspension cultures of Sf21 cells co expressing a CYP3A4 and NADPH-cytochrome P450 oxireductase were used to prepare the major metabolites of these compounds and revealed that oxidative N-dealkylation provided a pathway for formation of metabolites that were more agonistic than the parent partial agonists. Oxidative N-dealkylation was blocked in a new series of compounds, however oxidation alone was capable of producing full agonist metabolites. Incorporation of an ortho-primary amide and utilization of fluorine to modulate agonism afforded partial agonist MK-5932. Synthesis of the major metabolites of MK-5932 using bioreactor technology revealed that no significant GR-active metabolites were formed. Orally administered MK-5932 displayed anti-inflammatory efficacy in a Rat Oxazolone-induced chronic dermatitis model, while sparing plasma insulin. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.10.054