[1-[[4-[3-(6-Phenoxypyridazin-3-yl)propoxy]phenyl]methyl]piperidin-4-yl]methanol | 935692-56-1

• 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-[[4-[3-(6-Phenoxypyridazin-3-yl)propoxy]phenyl]methyl]piperidin-4-yl]methanol
• 英文别名: [1-[[4-[3-(6-phenoxypyridazin-3-yl)propoxy]phenyl]methyl]piperidin-4-yl]methanol
• CAS: 935692-56-1
• 化学式: C₂₆H₃₁N₃O₃
• 分子量: 433.55
• InChiKey: DARAALXZQWSOKR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  32
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  67.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-碘-6-苯氧基-哒嗪 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 氢气 、 三乙胺 、 二异丙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， -10.0~20.0 ℃ 、344.75 kPa 条件下， 生成 [1-[[4-[3-(6-Phenoxypyridazin-3-yl)propoxy]phenyl]methyl]piperidin-4-yl]methanol
  参考文献：
  名称：

  Design, synthesis and evaluation of MCH receptor 1 antagonists—Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition

  摘要：

  Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.05.074

文献信息

• Design, synthesis and evaluation of MCH receptor 1 antagonists—Part II: Optimization of pyridazines toward reduced phospholipidosis and hERG inhibition
  作者：Gerald J. Roth、Armin Heckel、Jörg T. Kley、Thorsten Lehmann、Stephan G. Müller、Thorsten Oost、Klaus Rudolf、Kirsten Arndt、Ralph Budzinski、Martin Lenter、Ralf R.H. Lotz、Marcus Schindler、Leo Thomas、Dirk Stenkamp

  DOI：10.1016/j.bmcl.2015.05.074

  日期：2015.8

  Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis. (C) 2015 Elsevier Ltd. All rights reserved.