tert-butyl (3R)-3-[[4-bromo-2-(2-hydroxyethoxy)phenyl]carbamoyl]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate | 1239903-04-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tert-butyl (3R)-3-[[4-bromo-2-(2-hydroxyethoxy)phenyl]carbamoyl]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 1239903-04-8
• 化学式: C₂₄H₂₉BrN₂O₆
• 分子量: 521.408
• InChiKey: KHCSJNAURJDWER-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  97.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-吡唑硼酸频哪醇酯 、 tert-butyl (3R)-3-[[4-bromo-2-(2-hydroxyethoxy)phenyl]carbamoyl]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.5h， 生成 tert-butyl (3R)-3-[[2-(2-hydroxyethoxy)-4-(1H-pyrazol-4-yl)phenyl]carbamoyl]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate
  参考文献：
  名称：

  Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase Inhibitors

  摘要：

  Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC(50) = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.

  DOI：

  10.1021/jm100579r
• 作为产物：
  描述：

  2-(2-Amino-5-bromophenoxy)ethan-1-ol 、 (3R)-6-methoxy-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-3-carboxylic acid 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 tert-butyl (3R)-3-[[4-bromo-2-(2-hydroxyethoxy)phenyl]carbamoyl]-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylate
  参考文献：
  名称：

  Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase Inhibitors

  摘要：

  Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC(50) = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.

  DOI：

  10.1021/jm100579r

文献信息

• Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase Inhibitors
  作者：Xingang Fang、Yan Yin、Yen Ting Chen、Lei Yao、Bo Wang、Michael D. Cameron、Li Lin、Susan Khan、Claudia Ruiz、Thomas Schröter、Wayne Grant、Amiee Weiser、Jennifer Pocas、Alok Pachori、Stephan Schürer、Philip LoGrasso、Yangbo Feng

  DOI：10.1021/jm100579r

  日期：2010.8.12

  Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC(50) = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.