1-[(2,4-Difluorophenyl)methyl]-6-[[4-methoxy-3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one | 1276037-88-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[(2,4-Difluorophenyl)methyl]-6-[[4-methoxy-3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one
• 英文别名: 1-[(2,4-difluorophenyl)methyl]-6-[4-methoxy-3-(trifluoromethyl)pyridin-2-yl]oxyquinazolin-4-one
• CAS: 1276037-88-7
• 化学式: C₂₂H₁₄F₅N₃O₃
• 分子量: 463.363
• InChiKey: KHJKIOVELDJAMF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  64
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2,4-二氟苯甲醛 在 sodium cyanoborohydride 、 potassium carbonate 、 溶剂黄146 作用下， 以 二甲基亚砜 为溶剂， 生成 1-[(2,4-Difluorophenyl)methyl]-6-[[4-methoxy-3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one
  参考文献：
  名称：

  Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype

  摘要：

  We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.037

文献信息

• Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype
  作者：Pierre L. Beaulieu、René Coulombe、Jianmin Duan、Gulrez Fazal、Cédrickx Godbout、Oliver Hucke、Araz Jakalian、Marc-André Joly、Olivier Lepage、Montse Llinàs-Brunet、Julie Naud、Martin Poirier、Nathalie Rioux、Bounkham Thavonekham、George Kukolj、Timothy A. Stammers

  DOI：10.1016/j.bmcl.2013.05.037

  日期：2013.7

  We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.