(E)-N’-(3,5-bis(trifluoromethyl)benzylidene)-4-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbohydrazide

• 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: (E)-N’-(3,5-bis(trifluoromethyl)benzylidene)-4-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbohydrazide
• 英文别名: N-[(E)-[3,5-bis(trifluoromethyl)phenyl]methylideneamino]-4-[3-(trifluoromethyl)anilino]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxamide
• 化学式: C₂₄H₁₇F₉N₆O
• 分子量: 576.424
• InChiKey: DVABPVRTTMPBGD-GVEJRPSDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  82.5
• 氢给体数：
  2
• 氢受体数：
  14

反应信息

• 作为产物：
  描述：

  1-苄基-4-哌啶酮-3-羧酸乙酯 在 palladium on activated charcoal 、 氢气 、 sodium methylate 、 氯化铵 、 一水合肼 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 反应 22.17h， 生成 (E)-N’-(3,5-bis(trifluoromethyl)benzylidene)-4-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carbohydrazide
  参考文献：
  名称：

  Optimization and evaluation of novel tetrahydropyrido[4,3-d]pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis

  摘要：

  Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and log with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while log exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-beta-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated lOg as an excellent anti-hepatofibrosis candidate, which reduced CCI4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.111904

文献信息

• Optimization and evaluation of novel tetrahydropyrido[4,3-d]pyrimidine derivatives as ATX inhibitors for cardiac and hepatic fibrosis
  作者：Nan Jiang、Yuhong Zhou、Minglin Zhu、Junlong Zhang、Meng Cao、Hongrui Lei、Ming Guo、Ping Gong、Guangyue Su、Xin Zhai

  DOI：10.1016/j.ejmech.2019.111904

  日期：2020.2

  Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and log with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while log exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-beta-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated lOg as an excellent anti-hepatofibrosis candidate, which reduced CCI4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs. (C) 2019 Elsevier Masson SAS. All rights reserved.