(R)-N-(2-(dimethylamino)ethyl)-4-methoxy-3-(4-((1-phenylethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: (R)-N-(2-(dimethylamino)ethyl)-4-methoxy-3-(4-((1-phenylethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide
• 英文别名: N-[2-(dimethylamino)ethyl]-4-methoxy-3-[4-[[(1R)-1-phenylethyl]amino]thieno[2,3-d]pyrimidin-6-yl]benzamide
• 化学式: C₂₆H₂₉N₅O₂S
• 分子量: 475.615
• InChiKey: DXLAGRLIXBCIQY-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-溴-4-甲氧基苯甲酸 在 2-双环己基膦-2',6'-二甲氧基联苯 、 双(乙腈)氯化钯(II) 、 四(三苯基膦)钯 、 硫酸 、 potassium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 24.0h， 生成 (R)-N-(2-(dimethylamino)ethyl)-4-methoxy-3-(4-((1-phenylethyl)amino)thieno[2,3-d]pyrimidin-6-yl)benzamide
  参考文献：
  名称：

  Extended structure–activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties

  摘要：

  Thieno[2,3-d]pyrimidines are attractive derivatives for cancer treatment, among others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.11.012

文献信息

• Extended structure–activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties
  作者：Steffen Bugge、Audun Formo Buene、Nathalie Jurisch-Yaksi、Ingri Ullestad Moen、Ellen Martine Skjønsfjell、Eirik Sundby、Bård Helge Hoff

  DOI：10.1016/j.ejmech.2015.11.012

  日期：2016.1

  Thieno[2,3-d]pyrimidines are attractive derivatives for cancer treatment, among others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents. (C) 2015 Elsevier Masson SAS. All rights reserved.