3'-(4-amino-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)biphenyl-4-carboxylic acid | 1345014-27-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3'-(4-amino-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)biphenyl-4-carboxylic acid
• 英文别名: 4-[3-(4-amino-5-oxo-7,8-dihydro-6H-1,6-naphthyridin-2-yl)phenyl]benzoic acid
• CAS: 1345014-27-8
• 化学式: C₂₁H₁₇N₃O₃
• 分子量: 359.384
• InChiKey: YSRPYHJBJBFZCI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-溴喹啉 、 3'-(4-amino-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)biphenyl-4-carboxylic acid 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 为溶剂， 以9%的产率得到3'-[5-oxo-4-(quinolin-5-ylamino)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl]biphenyl-4-carboxylic acid
  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.