3-(1-amino-1-methylethyl)-N-((2R)-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(trifluoromethyl)benzamide hydrochloride

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-(1-amino-1-methylethyl)-N-((2R)-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(trifluoromethyl)benzamide hydrochloride
• 英文别名: 3-(2-aminopropan-2-yl)-N-[(2R)-7-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl]-5-(trifluoromethyl)benzamide;hydrochloride
• 化学式: C₂₉H₂₉F₃N₄O₃*ClH
• 分子量: 575.03
• InChiKey: JHMJCTAQKGLPDD-ZMBIFBSDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.68
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  106
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  tert-butyl 3-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)benzoate 在 吡啶 、 盐酸 、 硫酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醚 、 乙二醇 为溶剂， 反应 77.08h， 生成 3-(1-amino-1-methylethyl)-N-((2R)-7-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl)-5-(trifluoromethyl)benzamide hydrochloride
  参考文献：
  名称：

  Design and Optimization of Potent and Orally Bioavailable Tetrahydronaphthalene Raf Inhibitors

  摘要：

  Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

  DOI：

  10.1021/jm101479y

文献信息

• Optimization of tetrahydronaphthalene inhibitors of Raf with selectivity over hERG
  作者：Shih-Chung Huang、Sharmila Adhikari、Roushan Afroze、Katherine Brewer、Emily F. Calderwood、Jouhara Chouitar、Dylan B. England、Craig Fisher、Katherine M. Galvin、Jeffery Gaulin、Paul D. Greenspan、Sean J. Harrison、Mi-Sook Kim、Steven P. Langston、Li-Ting Ma、Saurabh Menon、Hirotake Mizutani、Mansoureh Rezaei、Michael D. Smith、Dong Mei Zhang、Alexandra E. Gould

  DOI：10.1016/j.bmcl.2016.01.049

  日期：2016.2

  Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good

  对联芳醚支架的研究确定了具有良好体内活性的四氢萘Raf抑制剂。然而，这些化合物对hERG钾通道具有亲和力。本文中，我们描述了通过改变苯甲酰胺官能团上的取代基消除hERG活性的工作。所得化合物具有针对hERG通道的改进的选择性，良好的药代动力学性质并且在体内有效地抑制了Raf途径。