1-[(2,5-Difluorophenyl)methyl]-3-(2-methoxypyridin-3-yl)-5-methylindole-2-carboxylic acid | 1361147-51-4

• 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-[(2,5-Difluorophenyl)methyl]-3-(2-methoxypyridin-3-yl)-5-methylindole-2-carboxylic acid
• CAS: 1361147-51-4
• 化学式: C₂₃H₁₈F₂N₂O₃
• 分子量: 408.404
• InChiKey: IKMAVPWJXMPWOY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  64.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-[(2,5-Difluorophenyl)methyl]-3-(2-methoxypyridin-3-yl)-5-methylindole-2-carboxylic acid 在 盐酸 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 19.5h， 生成 1-[(2,5-difluorophenyl)methyl]-3-(1,2-dihydro-2-oxo-3-pyridinyl)-5-methyl-N-methylsulfonyl-1H-indole-2-carboxamide
  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
• 作为产物：
  描述：

  5-甲基吲哚-2-甲基酸酯 在 N-碘代丁二酰亚胺 、 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 水 、 potassium carbonate 、 caesium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 23.0h， 生成 1-[(2,5-Difluorophenyl)methyl]-3-(2-methoxypyridin-3-yl)-5-methylindole-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

• A Novel Class of Highly Potent Irreversible Hepatitis C Virus NS5B Polymerase Inhibitors
  作者：Kevin X. Chen、Charles A. Lesburg、Bancha Vibulbhan、Weiying Yang、Tin-Yau Chan、Srikanth Venkatraman、Francisco Velazquez、Qingbei Zeng、Frank Bennett、Gopinadhan N. Anilkumar、Jose Duca、Yueheng Jiang、Patrick Pinto、Li Wang、Yuhua Huang、Oleg Selyutin、Stephen Gavalas、Haiyan Pu、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/jm201322r

  日期：2012.3.8

  Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure–activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC50 = 1 nM). The formation of a covalent bond

  从基于吲哚的 C-3 吡啶酮 HCV NS5B 聚合酶抑制剂2 开始，进行了吲哚 N-1 苄基部分的构效关系 (SAR) 研究。该研究导致发现了具有对-氟-砜-或对-氟-硝基-取代的N-1苄基的不可逆抑制剂，其实现了突破性的复制子测定效力（EC 50 = 1 nM）。通过质谱和X射线晶体结构研究证明了与相邻的半胱氨酸366硫醇形成共价键。C-5乙基C-2羧酸衍生物47具有出色的口腔曲线下面积 (AUC) 为 18 μM·h (10 mg/kg)。它在猴子和狗中的口服暴露也非常好。NMR ALARM 分析、质谱实验、体外反筛选和毒理学分析表明，化合物47和蛋白质之间的共价键形成具有高度选择性和特异性。47的整体出色表现使其成为进一步调查的有趣候选者。
• 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.