2-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline-7-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 2-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline-7-carboxylic acid
• 英文别名: 2-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-fluoro-1-oxo-3-sulfanylidene-10,10a-dihydro-5H-imidazo[1,5-b]isoquinoline-7-carboxylic acid
• 化学式: C₁₉H₁₀F₄N₄O₃S
• 分子量: 450.373
• InChiKey: XUJUETPSTHNRTM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  31
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  130
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline-7-carboxylic acid 、 异丙醇胺 在 4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以62%的产率得到2-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-N-(1-hydroxypropan-2-yl)-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline-7-carboxamide
  参考文献：
  名称：

  Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists

  摘要：

  Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients. (c) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112196
• 作为产物：
  描述：

  2-氰基-5-硝基-3-(三氟甲基)吡啶 在 盐酸 、 铁粉 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 氯仿 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.0h， 生成 2-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-fluoro-1-oxo-3-thioxo-1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinoline-7-carboxylic acid
  参考文献：
  名称：

  Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists

  摘要：

  Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients. (c) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112196

文献信息

• Discovery of pyridine tetrahydroisoquinoline thiohydantoin derivatives with low blood-brain barrier penetration as the androgen receptor antagonists
  作者：Xi Xu、Qianming Du、Ying Meng、Zhiyu Li、Hongxi Wu、Yan Li、Zhili Zhao、Raoling Ge、Xiaoyu Lu、Siqi Xue、Xijing Chen、Yong Yang、Jubo Wang、Jinlei Bian

  DOI：10.1016/j.ejmech.2020.112196

  日期：2020.4

  Prostate cancer (PC) is the most diagnosed type of malignancy in men and the major frequently cause of cancer-related death worldwide. The androgen receptor (AR) has become a promising drug target for the treatment of PC. Here, we reported the design, optimization and evaluation of pyridine tetrahydroisoquinoline thiohydantoin derivatives with improved activity and safety as potent AR antagonists. The most promising compound 42f exhibited potent inhibitory activity on AR and strongly blocked AR nuclear translocation. Moreover, 42f displayed promising in vitro antitumor activity toward AR-dependent prostate cancer cell lines (LNCaP) and also demonstrated therapeutic effects in LNCaP xenograft tumor model in mice (TGI: 79%) with no apparent toxicity observed in vivo. More importantly, 42f showed negligible penetration of the brain-blood barrier (BBB) compared with enzalutamide. These results provide a foundation for the development of a new class of androgen receptor antagonists for potential therapeutics against PC with lower seizurogenic risk for patients. (c) 2020 Elsevier Masson SAS. All rights reserved.