3-hydroxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid 5-(4-fluoro-benzylamide) 2-methylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-hydroxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid 5-(4-fluoro-benzylamide) 2-methylamide
• 英文别名: N5-[(4-fluorophenyl)methyl]-3-hydroxy-N2-methyl-4-oxo-1H-pyridine-2,5-dicarboxamide；5-N-[(4-fluorophenyl)methyl]-3-hydroxy-2-N-methyl-4-oxo-1H-pyridine-2,5-dicarboxamide
• 化学式: C₁₅H₁₄FN₃O₄
• 分子量: 319.292
• InChiKey: APWZVVYVUZHKEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  108
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  methyl 4-(benzyloxy)-5-{((4-fluorobenzyl)carbanoyl)}-3-methoxypyridine-2-carboxylate 在 吡啶 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.58h， 生成 3-hydroxy-4-oxo-1,4-dihydro-pyridine-2,5-dicarboxylic acid 5-(4-fluoro-benzylamide) 2-methylamide
  参考文献：
  名称：

  Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding Pharmacophore

  摘要：

  Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.

  DOI：

  10.1021/jm3010459

文献信息

• Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding Pharmacophore
  作者：Takashi Kawasuji、Brian A. Johns、Hiroshi Yoshida、Teruhiko Taishi、Yoshiyuki Taoda、Hitoshi Murai、Ryuichi Kiyama、Masahiro Fuji、Tomokazu Yoshinaga、Takahiro Seki、Masanori Kobayashi、Akihiko Sato、Tamio Fujiwara

  DOI：10.1021/jm3010459

  日期：2012.10.25

  Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC50 and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.