1-(tert-butoxycarbonylamino)-7-(3-fluorophenyl)isoquinoline-4-carboxylic acid | 1449278-81-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 1-(tert-butoxycarbonylamino)-7-(3-fluorophenyl)isoquinoline-4-carboxylic acid
• 英文别名: 7-(3-Fluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonylamino]isoquinoline-4-carboxylic acid；7-(3-fluorophenyl)-1-[(2-methylpropan-2-yl)oxycarbonylamino]isoquinoline-4-carboxylic acid
• CAS: 1449278-81-2
• 化学式: C₂₁H₁₉FN₂O₄
• 分子量: 382.391
• InChiKey: XICYPWBMKXPYPB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  88.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(tert-butoxycarbonylamino)-7-(3-fluorophenyl)isoquinoline-4-carboxylic acid 在 盐酸 、 sodium tetrahydroborate 、 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 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 6.0h， 生成 1-amino-7-(3-fluorophenyl)-N-(3-hydroxycyclobutyl)isoquinoline-4-carboxamide
  参考文献：
  名称：

  Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

  摘要：

  Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.

  DOI：

  10.1021/acsmedchemlett.5b00174
• 作为产物：
  描述：

  7-溴-1-氯异喹啉 在 N-甲基吡咯烷酮 、 4-二甲氨基吡啶 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 ammonium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 sodium carbonate 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 148.0 ℃ 、344.75 kPa 条件下， 反应 86.0h， 生成 1-(tert-butoxycarbonylamino)-7-(3-fluorophenyl)isoquinoline-4-carboxylic acid
  参考文献：
  名称：

  Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

  摘要：

  Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.

  DOI：

  10.1021/acsmedchemlett.5b00174

文献信息

• [EN] ISOQUINOLINE AND NAPHTHYRIDINE DERIVATIVES<br/>[FR] DÉRIVÉS D'ISOQUINOLÉINE ET DE NAPHTYRIDINE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2013113669A1

  公开（公告）日：2013-08-08

  The invention provides novel compounds having the general formula(I) wherein A, R1 and R2 are as described herein, compositions including the compounds and use of the compounds for inhibiting angiogenesis by inhibition of MAP4K4.

  该发明提供了具有一般式(I)的新化合物，其中A、R1和R2如本文所述，包括这些化合物的组合物以及利用这些化合物通过抑制MAP4K4来抑制血管生成。
• US20140343036A1
  申请人：——

  公开号：US20140343036A1

  公开（公告）日：2014-11-20
• US9586956B2
  申请人：——

  公开号：US9586956B2

  公开（公告）日：2017-03-07
• Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis
  作者：Chudi O. Ndubaku、Terry D. Crawford、Huifen Chen、Jason W. Boggs、Joy Drobnick、Seth F. Harris、Rajiv Jesudason、Erin McNamara、Jim Nonomiya、Amy Sambrone、Stephen Schmidt、Tanya Smyczek、Philip Vitorino、Lan Wang、Ping Wu、Stacey Yeung、Jinhua Chen、Kevin Chen、Charles Z. Ding、Tao Wang、Zijin Xu、Stephen E. Gould、Lesley J. Murray、Weilan Ye

  DOI：10.1021/acsmedchemlett.5b00174

  日期：2015.8.13

  Diverse biological roles for mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) have necessitated the identification of potent inhibitors in order to study its function in various disease contexts. In particular, compounds that can be used to carry out such studies in vivo would be critical for elucidating the potential for therapeutic intervention. A structure-based design effort coupled with property-guided optimization directed at minimizing the ability of the inhibitors to cross into the CNS led to an advanced compound 13 (GNE-495) that showed excellent potency and good PK and was used to demonstrate in vivo efficacy in a retinal angiogenesis model recapitulating effects that were observed in the inducible Map4k4 knockout mice.