6-(2-methoxyphenyl)pyrimidin-4(3H)-one | 1105195-48-9

• 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: 6-(2-methoxyphenyl)pyrimidin-4(3H)-one
• 英文别名: 6-(2-Methoxyphenyl)pyrimidin-4-ol；4-(2-methoxyphenyl)-1H-pyrimidin-6-one
• CAS: 1105195-48-9
• 化学式: C₁₁H₁₀N₂O₂
• 分子量: 202.213
• InChiKey: FBIIBEODPZRTLJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  50.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-(2-methoxyphenyl)pyrimidin-4(3H)-one 在 bis-triphenylphosphine-palladium(II) chloride 、 三溴化硼 、 sodium carbonate 、 potassium carbonate 、 potassium iodide 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 34.5h， 生成 3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)benzyl)oxy)phenyl)pyrimidin-4(3H)-one
  参考文献：
  名称：

  4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M₁ Muscarinic Acetylcholine Receptor

  摘要：

  Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimers and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M-1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.

  DOI：

  10.1021/acs.jmedchem.5b01562
• 作为产物：
  描述：

  6-氯嘧啶-4(3H)-酮 、 2-甲氧基苯基硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 48.0h， 以20%的产率得到6-(2-methoxyphenyl)pyrimidin-4(3H)-one
  参考文献：
  名称：

  4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M₁ Muscarinic Acetylcholine Receptor

  摘要：

  Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimers and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M-1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.

  DOI：

  10.1021/acs.jmedchem.5b01562

文献信息

• 4-Phenylpyridin-2-one Derivatives: A Novel Class of Positive Allosteric Modulator of the M₁ Muscarinic Acetylcholine Receptor
  作者：Shailesh N. Mistry、Manuela Jörg、Herman Lim、Natalie B. Vinh、Patrick M. Sexton、Ben Capuano、Arthur Christopoulos、J. Robert Lane、Peter J. Scammells

  DOI：10.1021/acs.jmedchem.5b01562

  日期：2016.1.14

  Positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (M1 mAChR) are a promising strategy for the treatment of the cognitive deficits associated with diseases including Alzheimers and schizophrenia. Herein, we report the design, synthesis, and characterization of a novel family of M-1 mAChR PAMs. The most active compounds of the 4-phenylpyridin-2-one series exhibited comparable binding affinity to the reference compound, 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA) (1), but markedly improved positive cooperativity with acetylcholine, and retained exquisite selectivity for the M1 mAChR. Furthermore, our pharmacological characterization revealed ligands with a diverse range of activities, including modulators that displayed both high intrinsic efficacy and PAM activity, those that showed no detectable agonism but robust PAM activity and ligands that displayed robust allosteric agonism but little modulatory activity. Thus, the 4-phenylpyridin-2-one scaffold offers an attractive starting point for further lead optimization.
• 6-Phenylpyrimidin-4-ones as Positive Allosteric Modulators at the M₁ mAChR: The Determinants of Allosteric Activity
  作者：Manuela Jörg、Emma T. van der Westhuizen、Elham Khajehali、Wessel A. C. Burger、Jonathan M. White、Kwok H. C. Choy、Andrew B. Tobin、Patrick M. Sexton、Celine Valant、Ben Capuano、Arthur Christopoulos、Peter J. Scammells

  DOI：10.1021/acschemneuro.8b00613

  日期：2019.3.20

  Targeting allosteric sites of the M-1 muscarinic acetylcholine receptor (mAChR) is an enticing approach to overcome the lack of receptor subtype selectivity observed with orthosteric ligands. This is a promising strategy for obtaining novel therapeutics to treat cognitive deficits observed in Alzheimer's disease and schizophrenia, while reducing the peripheral side effects such as seen in the current treatment regimes, which are non-subtype selective. We previously described compound 2, the first positive allosteric modulator (PAM) of the M-1 mAChR based on a 6-phenylpyrimidin-4-one scaffold, which has been further developed in this study. Herein, we present the synthesis, characterization, and pharmacological evaluation of a series of 6-phenylpyrimidin-4-ones with modifications to the 4-(1-methylpyrazol-4-yl)benzyl pendant. Selected compounds, BQCA, 1, 2, 9i, 13, 14b, 15c, and 15d, were further profiled in terms of their allosteric affinity, cooperativity with acetylcholine (ACh), and intrinsic efficacy. Additionally, 2 and 9i were tested in mouse primary cortical neurons, displaying various degrees of intrinsic agonism and potentiation of the acetylcholine response. Overall, the results suggest that the pendant moiety is important for allosteric binding affinity and the direct agonistic efficacy of the 6-phenylpyrimidin-4-one based M-1 mAChR PAMs.