2-(3-methylpyridin-2-yl)-5-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one hydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-(3-methylpyridin-2-yl)-5-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one hydrochloride
• 英文别名: 2-(3-methylpyridin-2-yl)-5-[4-[3-[(2R)-2-methylpyrrolidin-1-yl]propoxy]phenyl]pyridazin-3-one;hydrochloride
• 化学式: C₂₄H₂₈N₄O₂*(x)ClH
• 分子量: 441.0
• InChiKey: JLNMPLDXGXEPTH-FSRHSHDFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.28
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  58
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对甲氧基苯乙醇 在 盐酸 、 copper(l) iodide 、 水 、 吗啡啉盐酸盐 、 三溴化硼 、 potassium carbonate 、 戴斯-马丁氧化剂 、 一水合肼 、 sodium iodide 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 为溶剂， 反应 49.0h， 生成 2-(3-methylpyridin-2-yl)-5-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one hydrochloride
  参考文献：
  名称：

  Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H₃ Receptor Antagonists with Potent Cognition Enhancing Activity

  摘要：

  Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K-i = 2.8 nM) and rat H(3)Rs (rH(3)R K-i = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R-2 and R-6 positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH3R K-i = 1.7 nM, rH(3)R K = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H3R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.

  DOI：

  10.1021/jm201295j

文献信息

• Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H₃ Receptor Antagonists with Potent Cognition Enhancing Activity
  作者：Ming Tao、Lisa D. Aimone、Zeqi Huang、Joanne Mathiasen、Rita Raddatz、Jacquelyn Lyons、Robert L. Hudkins

  DOI：10.1021/jm201295j

  日期：2012.1.12

  Previous studies have shown that (5-4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K-i = 2.8 nM) and rat H(3)Rs (rH(3)R K-i = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R-2 and R-6 positions to improve the pharmacokinetic properties over 2 led to the identification of 5-4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH3R K-i = 1.7 nM, rH(3)R K = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H3R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.