(S)-3-(neopentyloxy)-7-(pyrimidin-5-yl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine | 1215870-16-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (S)-3-(neopentyloxy)-7-(pyrimidin-5-yl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine
• 英文别名: (5S)-7-(5-pyrimidinyl)-3-(2,2-dimethylpropoxy)-spiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazol]-2'-amine；(4S)-3'-(2,2-dimethylpropoxy)-7'-pyrimidin-5-ylspiro[5H-1,3-oxazole-4,5'-chromeno[2,3-b]pyridine]-2-amine
• CAS: 1215870-16-8
• 化学式: C₂₃H₂₃N₅O₃
• 分子量: 417.467
• InChiKey: RZWUVNLTQGLJCA-QHCPKHFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  新戊基碘 在 dichloro bis((p-dimethylaminophenyl)-ϖ-di-tert-butylphosphine)palladium(II) 、 potassium carbonate 、 caesium carbonate 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (S)-3-(neopentyloxy)-7-(pyrimidin-5-yl)-5'H-spiro[chromeno[2,3-b]pyridine-5,4'-oxazol]-2'-amine
  参考文献：
  名称：

  Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)

  摘要：

  We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain A beta levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

  DOI：

  10.1021/jm5012676

文献信息

• Inhibitors of β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (<i>S</i>)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5′<i>H</i>-spiro[chromeno[2,3-<i>b</i>]pyridine-5,4′-oxazol]-2′-amine (AMG-8718)
  作者：Thomas A. Dineen、Kui Chen、Alan C. Cheng、Katayoun Derakhchan、Oleg Epstein、Joel Esmay、Dean Hickman、Chuck E. Kreiman、Isaac E. Marx、Robert C. Wahl、Paul H. Wen、Matthew M. Weiss、Douglas A. Whittington、Stephen Wood、Robert T. Fremeau、Ryan D. White、Vinod F. Patel

  DOI：10.1021/jm5012676

  日期：2014.12.11

  We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain A beta levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.