N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-acetamide hydrochloride | 1082056-68-5

• 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: N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-acetamide hydrochloride
• 英文别名: N-[2-(3,5-dimethylpyrazol-1-yl)-6-(5-methoxypyridin-3-yl)pyrimidin-4-yl]acetamide;hydrochloride
• CAS: 1082056-68-5
• 化学式: C₁₇H₁₈N₆O₂*ClH
• 分子量: 374.83
• InChiKey: SOOBUFQCWMTOFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.73
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  94.8
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-acetamide 在 盐酸 作用下， 以 hexafluoropropan-2-ol 、 乙醚 为溶剂， 生成 N-[2-(3,5-dimethyl-pyrazol-1-yl)-6-(5-methoxy-pyridin-3-yl)-pyrimidin-4-yl]-acetamide hydrochloride
  参考文献：
  名称：

  Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A_2A Adenosine Receptor Antagonists for the Treatment of Parkinson’s Disease

  摘要：

  4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA(2A) receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA(2A) K-i 2.3 nM, hA(1) K-i 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA(2A) K-i 0.83 nM, hA(1) K-i 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA(2A) K-i 0.44 nM, hA(1) K-i 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation Of L-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.

  DOI：

  10.1021/jm800851u

文献信息

• Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A_2A Adenosine Receptor Antagonists for the Treatment of Parkinson’s Disease
  作者：Xiaohu Zhang、John E. Tellew、Zhiyong Luo、Manisha Moorjani、Emily Lin、Marion C. Lanier、Yongsheng Chen、John P. Williams、John Saunders、Sandra M. Lechner、Stacy Markison、Tanya Joswig、Robert Petroski、Jaime Piercey、William Kargo、Siobhan Malany、Mark Santos、Raymond S. Gross、Jenny Wen、Kayvon Jalali、Zhihong O’Brien、Carol E. Stotz、María I. Crespo、José-Luis Díaz、Deborah H. Slee

  DOI：10.1021/jm800851u

  日期：2008.11.27

  4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA(2A) receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA(2A) K-i 2.3 nM, hA(1) K-i 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA(2A) K-i 0.83 nM, hA(1) K-i 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA(2A) K-i 0.44 nM, hA(1) K-i 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation Of L-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.