perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate
• 英文别名: Perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate；(2,3,4,5,6-pentafluorophenyl) 1-[5-chloro-4-(3-fluorophenyl)-2-methoxyphenyl]isoquinoline-6-sulfonate
• 化学式: C₂₈H₁₄ClF₆NO₄S
• 分子量: 609.933
• InChiKey: WRLNVKUKMLKJSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  41
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  73.9
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  哒嗪-3-胺 、 perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate 在 sodium hexamethyldisilazane 、 盐酸 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 0.17h， 以72%的产率得到1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(pyridazin-3-yl)isoquinoline-6-sulfonamide hydrochloride
  参考文献：
  名称：

  Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities

  摘要：

  Several reports have recently emerged regarding the identification of heteroarylsulfonamides as Na(V)1.7 inhibitors that demonstrate high levels of selectivity over other Na-V isoforms. The optimization of a series of internal Na(V)1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.

  DOI：

  10.1021/acs.jmedchem.6b01851
• 作为产物：
  描述：

  1-氯-6-溴异喹啉 在 tris-(dibenzylideneacetone)dipalladium(0) 、 四(三苯基膦)钯 、 1,3-二氯-5,5-二甲基海因 、 potassium carbonate 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 、 水 、 乙腈 为溶剂， 反应 4.5h， 生成 perfluorophenyl 1-(2-chloro-3'-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)isoquinoline-6-sulfonate
  参考文献：
  名称：

  Sulfonamides as Selective Na_V1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities

  摘要：

  Several reports have recently emerged regarding the identification of heteroarylsulfonamides as Na(V)1.7 inhibitors that demonstrate high levels of selectivity over other Na-V isoforms. The optimization of a series of internal Na(V)1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.

  DOI：

  10.1021/acs.jmedchem.6b01851

文献信息

• Bicyclic Aryl and Heteroaryl Sodium Channel Inhibitors
  申请人：Amgen Inc.

  公开号：US20130150339A1

  公开（公告）日：2013-06-13

  The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

  本发明提供了式I的化合物或其药学上可接受的盐，它们是电压门控钠通道抑制剂，特别是Nav 1.7的抑制剂。这些化合物用于治疗可通过钠通道抑制治疗的疾病，如疼痛性疾病。同时提供了含有本发明化合物的药物组合物。
• Bicyclic aryl and heteroaryl sodium channel inhibitors
  申请人：Amgen Inc.

  公开号：US09012443B2

  公开（公告）日：2015-04-21

  The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

  本发明提供了公式I的化合物或其药学上可接受的盐，它们是电压门控钠通道抑制剂，特别是Nav 1.7的抑制剂。这些化合物对于治疗可通过钠通道抑制治疗的疾病，如疼痛障碍，是有用的。还提供了含有本发明化合物的制药组合物。
• Bicyclic Sulfonamide Compounds as Sodium Channel Inhibitors
  申请人：AMGEN INC.

  公开号：US20160137636A1

  公开（公告）日：2016-05-19

  The present invention provides compounds of Formula I or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

  本发明提供了I式化合物或其药学上可接受的盐，其为电压门控钠通道抑制剂，特别是Nav1.7。该化合物可用于治疗可通过钠通道抑制治疗的疾病，如疼痛障碍。还提供了含有本发明化合物的制药组合物。
• BICYCLIC ARYL AND HETEROARYL SODIUM CHANNEL INHIBITORS
  申请人：AMGEN, INC.

  公开号：EP2788332A1

  公开（公告）日：2014-10-15
• US9012443B2
  申请人：——

  公开号：US9012443B2

  公开（公告）日：2015-04-21