4-(methylsulfonyl)-2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one | 1345014-20-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 4-(methylsulfonyl)-2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one
• 英文别名: 4-methylsulfonyl-2-phenyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
• CAS: 1345014-20-1
• 化学式: C₁₄H₁₃N₃O₃S
• 分子量: 303.342
• InChiKey: FHUHJXKWNZPLQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  97.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(methylsulfonyl)-2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one 、 间氨基苯甲醚 以 乙醇 为溶剂， 反应 9.0h， 生成 4-[(3-methoxyphenyl)amino]-2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one
  参考文献：
  名称：

  4-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships

  摘要：

  Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

  DOI：

  10.1021/acs.jmedchem.7b01751
• 作为产物：
  描述：

  tert-butyl 4-(methylthio)-5-oxo-2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成 4-(methylsulfonyl)-2-phenyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one
  参考文献：
  名称：

  4-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships

  摘要：

  Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.

  DOI：

  10.1021/acs.jmedchem.7b01751

文献信息

• New 7,8-dihydro-1,6-naphthyridin-5(6h)-one-derivatives as PDE4 inhibitors
  申请人：Almirall, S.A.

  公开号：EP2380890A1

  公开（公告）日：2011-10-26

  New 7,8-dihydro-1,6-naphthyridin-5(6H)-one derivatives derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of the phosphodiesterase IV (PDE4).

  揭示了具有化学结构式（I）的新的7,8-二氢-1,6-萘啶-5(6H)-酮衍生物衍生物；以及它们的制备方法，包含它们的药物组合物以及它们作为磷酸二酯酶IV（PDE4）抑制剂在治疗中的用途。
• 4-Amino-7,8-dihydro-1,6-naphthyridin-5(6<i>H</i>)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships
  作者：Richard S. Roberts、Sara Sevilla、Manel Ferrer、Joan Taltavull、Begoña Hernández、Victor Segarra、Jordi Gràcia、Martin D. Lehner、Amadeu Gavaldà、Miriam Andrés、Judit Cabedo、Dolors Vilella、Peter Eichhorn、Elena Calama、Carla Carcasona、Montserrat Miralpeix

  DOI：10.1021/acs.jmedchem.7b01751

  日期：2018.3.22

  Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose-response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose-response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.