1-[(2-amino-4-pyridyl)methyl]-5-hydroxy-3-(2-oxo-1H-pyridin-3-yl)indole-2-carboxylic acid | 1354329-50-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-[(2-amino-4-pyridyl)methyl]-5-hydroxy-3-(2-oxo-1H-pyridin-3-yl)indole-2-carboxylic acid
• 英文别名: 1-[(2-aminopyridin-4-yl)methyl]-5-hydroxy-3-(2-oxo-1H-pyridin-3-yl)indole-2-carboxylic acid
• CAS: 1354329-50-2
• 化学式: C₂₀H₁₆N₄O₄
• 分子量: 376.371
• InChiKey: INSLVEBTRGPZJP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  131
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-甲氧基吡啶基-3-硼酸 在 盐酸 、 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 水 、 potassium carbonate 、 caesium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 39.0h， 生成 1-[(2-amino-4-pyridyl)methyl]-5-hydroxy-3-(2-oxo-1H-pyridin-3-yl)indole-2-carboxylic acid
  参考文献：
  名称：

  Structure–Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase

  摘要：

  Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC50 = 0.008 mu M) and cell-based replicon (EC50 = 0.02 mu M) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 mu M.h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.

  DOI：

  10.1021/jm201258k

文献信息

• Structure–Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase
  作者：Kevin X. Chen、Bancha Vibulbhan、Weiying Yang、Mousumi Sannigrahi、Francisco Velazquez、Tin-Yau Chan、Srikanth Venkatraman、Gopinadhan N. Anilkumar、Qingbei Zeng、Frank Bennet、Yueheng Jiang、Charles A. Lesburg、Jose Duca、Patrick Pinto、Stephen Gavalas、Yuhua Huang、Wanli Wu、Oleg Selyutin、Sony Agrawal、Boris Feld、Hsueh-Cheng Huang、Cheng Li、Kuo-Chi Cheng、Neng-Yang Shih、Joseph A. Kozlowski、Stuart B. Rosenblum、F. George Njoroge

  DOI：10.1021/jm201258k

  日期：2012.1.26

  Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2' or 5' positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC50 = 0.008 mu M) and cell-based replicon (EC50 = 0.02 mu M) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 mu M.h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.