5-Ethyl-9-hydroxymethyl-7-(3-methoxy-phenyl)-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a,d]cyclohepten-11-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-Ethyl-9-hydroxymethyl-7-(3-methoxy-phenyl)-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a,d]cyclohepten-11-one
• 英文别名: Nevirapin 2,4-Disubstituted deriv. 13e；2-ethyl-7-(hydroxymethyl)-5-(3-methoxyphenyl)-2,4,9,15-tetrazatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-10-one
• 化学式: C₂₁H₂₀N₄O₃
• 分子量: 376.415
• InChiKey: ZNKSHDABFQKUJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  87.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-amino-4-(2-(1,3-dioxanyl))-2,6-dimethoxypyridine 在 吡啶 、 2,4,6-三甲基吡啶 、 bis-triphenylphosphine-palladium(II) chloride 、 sodium tetrahydroborate 、 二乙基异丙基胺 、 sodium hexamethyldisilazane 、 溶剂黄146 、 N,N-二异丙基乙胺 、 lithium chloride 、 lithium iodide 作用下， 以 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 0.25h， 生成 5-Ethyl-9-hydroxymethyl-7-(3-methoxy-phenyl)-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a,d]cyclohepten-11-one
  参考文献：
  名称：

  Novel Non-nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. 5. 4-Substituted and 2,4-Disubstituted Analogs of Nevirapine

  摘要：

  Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-PT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.

  DOI：

  10.1021/jm00024a011

文献信息

• Novel Non-nucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. 5. 4-Substituted and 2,4-Disubstituted Analogs of Nevirapine
  作者：Terence A. Kelly、John R. Proudfoot、Daniel W. McNeil、Usha R. Patel、Eva David、Karl D. Hargrave、Peter M. Grob、Mario Cardozo、Atul Agarwal、Julian Adams

  DOI：10.1021/jm00024a011

  日期：1995.11

  Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-PT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.