(2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide | 1450618-59-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide
• 英文别名: (E)-3-(2-ethyl-6-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-7-yl)-N-hydroxyacrylamide；(E)-3-[2-ethyl-6-fluoro-4-oxo-3-(2-phenylethyl)quinazolin-7-yl]-N-hydroxyprop-2-enamide
• CAS: 1450618-59-3
• 化学式: C₂₁H₂₀FN₃O₃
• 分子量: 381.407
• InChiKey: RGKDACUEVSPDNA-CMDGGOBGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  82
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-chloro-5-fluoro-2-(propionamide)benzoic acid 在 吡啶 、 亚磷酸三苯酯 、 trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) 、 N-甲基二环己基胺 、 盐酸羟胺 、 potassium hydroxide 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.25h， 生成 (2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide
  参考文献：
  名称：

  Quinazolin-4-one Derivatives as Selective Histone Deacetylase-6 Inhibitors for the Treatment of Alzheimer’s Disease

  摘要：

  Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4h, NHis the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of g-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated beta-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydroquinazolin-7-yl)-acrylarnide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50,29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 mu M) or cytochrome P450 activity (IC50 >63 mu M) in vitro, and significantly improves learning-based performances of mice with beta-amyloid-induced hippocampal lesions.

  DOI：

  10.1021/jm400564j

文献信息

• HISTONE DEACETYLASES (HDACS) INHIBITORS
  申请人：ANNJI PHARMACEUTICAL CO., LTD.

  公开号：US20130267542A1

  公开（公告）日：2013-10-10

  Histone deacetylases inhibitors (HDACIs) and compositions comprising the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit are also disclosed.

  揭示了组蛋白去乙酰化酶抑制剂（HDACIs）和包含其的组合物。还公开了通过抑制HDAC来获益的治疗疾病和病况的方法。
• US9155739B2
  申请人：——

  公开号：US9155739B2

  公开（公告）日：2015-10-13
• US9387209B2
  申请人：——

  公开号：US9387209B2

  公开（公告）日：2016-07-12
• [EN] HISTONE DEACETYLASES (HDACS) INHIBITORS<br/>[FR] INHIBITEURS D'HISTONE DÉSACÉTYLASES (HDAC)
  申请人：ANNJI PHARM CO LTD

  公开号：WO2013154870A1

  公开（公告）日：2013-10-17

  Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit are also disclosed. In an embodiment of the invention, the compound is (2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquina20lin-7-yl)-N-hydroxyacrylamide, or a salt thereof. In another embodiment of the invention, the compound is (2E)-3-(2-ethyl-7-f1uoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide, (2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide, or a salt thereof. In another aspect the invention relates to a composition comprising a therapeutically effective amount of a compound as aforementioned, or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, and a pharmaceutically acceptable carrier or vehicle.
• Quinazolin-4-one Derivatives as Selective Histone Deacetylase-6 Inhibitors for the Treatment of Alzheimer’s Disease
  作者：Chao-Wu Yu、Pei-Teh Chang、Ling-Wei Hsin、Ji-Wang Chern

  DOI：10.1021/jm400564j

  日期：2013.9.12

  Novel quinazolin-4-one derivatives containing a hydroxamic acid moiety were designed and synthesized. All compounds were subjected to histone deacetylase (HDAC) enzymatic assays to identify selective HDAC6 inhibitors with nanomolar IC50 values. (E)-3-(2-Ethyl-7-fluoro-4-oxo-3-phenethyl-3,4-dihydroquinazolin-6-yl)-N-hydroxyacrylamide, 4h, NHis the most potent HDAC6 inhibitor (IC50, 8 nM). In vitro, these compounds induced neurite outgrowth accompanied by growth-associated protein 43 expression, and they enhanced the synaptic activities of PC12 and SH-SY5Y neuronal cells without producing toxic or mitogenic effects. Several of the compounds dramatically increased nonhistone protein acetylation, specifically of g-tubulin. Some of the more potent HDAC6 inhibitors decreased zinc-mediated beta-amyloid aggregation in vitro. N-Hydroxy-3-(2-methyl-4-oxo-3-phenethyl-3,4-dihydroquinazolin-7-yl)-acrylarnide, 3f, the most promising drug candidate, selectively inhibits HDAC6 (IC50,29 nM), practically does not affect human ether-a-go-go-related membrane channel activity (IC50 >10 mu M) or cytochrome P450 activity (IC50 >63 mu M) in vitro, and significantly improves learning-based performances of mice with beta-amyloid-induced hippocampal lesions.