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

文献信息

• Discovery and Characterization of (<i>R</i>)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-<i>c</i>][1,4]oxazin-4(9<i>H</i>)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates
  作者：Antonia F. Stepan、Michelle M. Claffey、Matthew R. Reese、Gayatri Balan、Gabriela Barreiro、Jason Barricklow、Michael J. Bohanon、Brian P. Boscoe、Gregg D. Cappon、Lois K. Chenard、Julie Cianfrogna、Laigao Chen、Karen J. Coffman、Susan E. Drozda、Joshua R. Dunetz、Somraj Ghosh、Xinjun Hou、Christopher Houle、Kapil Karki、John T. Lazzaro、Jessica Y. Mancuso、John M. Marcek、Emily L. Miller、Mark A. Moen、Steven O’Neil、Isao Sakurada、Marc Skaddan、Vinod Parikh、Deborah L. Smith、Patrick Trapa、Jamison B. Tuttle、Patrick R. Verhoest、Daniel P. Walker、Annie Won、Ann S. Wright、Jessica Whritenour、Kenneth Zasadny、Margaret M. Zaleska、Lei Zhang、Christopher L. Shaffer

  DOI：10.1021/acs.jmedchem.7b00604

  日期：2017.9.28

  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.