PF-06462894

• 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: PF-06462894
• 英文别名: (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one；(6R)-6-(2,2-dimethylpropyl)-2-(pyridin-2-ylmethoxy)-7,9-dihydro-6H-pyrimido[2,1-c][1,4]oxazin-4-one
• 化学式: C₁₈H₂₃N₃O₃
• 分子量: 329.399
• InChiKey: QDIYOEYPJWXMRN-CQSZACIVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  64
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-叔丁基-D-Β-丙氨酸/(R)-3-氨基-4,4-二甲基戊酸 在 lithium aluminium tetrahydride 、 偶氮二甲酸二异丙酯 、 potassium tert-butylate 、 sodium methylate 、 potassium carbonate 、 氯化铵 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 46.5h， 生成 PF-06462894
  参考文献：
  名称：

  Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates

  摘要：

  We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu(5) negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu(5) NAMs. Increasing the sp(3) character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu(5) NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c] [1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.

  DOI：

  10.1021/acs.jmedchem.7b00604