1-(3-(3-chlorophenyl)-4-methoxybenzyl)-3-methyl-piperidine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-(3-(3-chlorophenyl)-4-methoxybenzyl)-3-methyl-piperidine
• 化学式: C₂₀H₂₄ClNO
• 分子量: 329.9
• InChiKey: WXTKZPYCIMNDEU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  3-溴-4-甲氧基苯甲醛 在 sodium tetrahydroborate 、 potassium phosphate 、 四(三苯基膦)钯 、 三溴化磷 、 potassium carbonate 作用下， 以 甲醇 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 38.0h， 生成 1-(3-(3-chlorophenyl)-4-methoxybenzyl)-3-methyl-piperidine
  参考文献：
  名称：

  Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect

  摘要：

  Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds 11r and 11s with mid-nanomolar IC50 values partially bind to PDE4B1 (I-max = 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds lir and Us were found to alleviate cellular apoptosis in SH-SY5Y cells induced by MPP+ (1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 inhibitor rolipram. Furthermore, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%). (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.02.026

文献信息

• Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect
  作者：Lv Tang、Chang Huang、Jiahong Zhong、JiaPeng He、Jiayin Guo、Menghua Liu、Jiang-Ping Xu、Hai-Tao Wang、Zhong-Zhen Zhou

  DOI：10.1016/j.ejmech.2019.02.026

  日期：2019.4

  Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds 11r and 11s with mid-nanomolar IC50 values partially bind to PDE4B1 (I-max = 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds lir and Us were found to alleviate cellular apoptosis in SH-SY5Y cells induced by MPP+ (1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 inhibitor rolipram. Furthermore, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%). (C) 2019 Elsevier Masson SAS. All rights reserved.