5-fluoro-2-{5-[1-(4-fluorophenyl)-5-methyl-1H-indazol-6-yl]-3-oxopentyl}benzoic acid | 1352240-46-0

• 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-{5-[1-(4-fluorophenyl)-5-methyl-1H-indazol-6-yl]-3-oxopentyl}benzoic acid
• 英文别名: 5-Fluoro-2-[5-[1-(4-fluorophenyl)-5-methylindazol-6-yl]-3-oxopentyl]benzoic acid；5-fluoro-2-[5-[1-(4-fluorophenyl)-5-methylindazol-6-yl]-3-oxopentyl]benzoic acid
• CAS: 1352240-46-0
• 化学式: C₂₆H₂₂F₂N₂O₃
• 分子量: 448.469
• InChiKey: DLUYVJPDWRVKQB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  72.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (4aS,5R)-5-ethynyl-1-(4-fluorophenyl)-4a-methyl-1,4,4a,5,6,7-hexahydrocyclopenta[f]indazol-5-ol 在 copper(l) iodide 、 四(三苯基膦)钯 、 sodium bismuthate 、 palladium 10% on activated carbon 、 水 、 氢气 、 溶剂黄146 、 二异丙胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 3.5h， 生成 5-fluoro-2-{5-[1-(4-fluorophenyl)-5-methyl-1H-indazol-6-yl]-3-oxopentyl}benzoic acid
  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

文献信息

• Discovery of selective glucocorticoid receptor modulator MK-5932
  作者：Christopher J. Bungard、George D. Hartman、Jesse J. Manikowski、James J. Perkins、Chang Bai、Philip E. Brandish、Danielle H. Euler、James C. Hershey、Azriel Schmidt、Yulin Fang、Ryan T. Norcross、Tom H. Rushmore、Charles D. Thompson、Robert S. Meissner

  DOI：10.1016/j.bmc.2011.10.054

  日期：2011.12

  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.