(S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthen]-2-amine | 1215869-82-1

• 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)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthen]-2-amine
• 英文别名: (4S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(3-pyridinyl)spiro[1,3-oxazole-4,9'-xanthen]-2-amine；(4S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)spiro[5H-1,3-oxazole-4,9'-xanthene]-2-amine
• CAS: 1215869-82-1
• 化学式: C₂₄H₂₀F₃N₃O₃
• 分子量: 455.436
• InChiKey: FINMGPWGVROOTC-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  79
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2,5-二溴苯甲酸 在 (CuOTf)*toluene 、 二氧化碳 、 碘 、 三溴化硼 、 sodium carbonate 、 caesium carbonate 、 二乙胺 、 sodium iodide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 甲苯 、 正戊烷 为溶剂， 反应 61.69h， 生成 (S)-4'-fluoro-2'-(2-fluoro-2-methylpropoxy)-7'-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9'-xanthen]-2-amine
  参考文献：
  名称：

  Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors

  摘要：

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

  DOI：

  10.1021/jm501266w

文献信息

• SPIRO-TETRACYCLIC RING COMPOUNDS AS BETASECRETASE MODULATORS AND METHODS OF USE
  申请人：Amgen Inc.

  公开号：EP2328903B1

  公开（公告）日：2014-03-05
• Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors
  作者：Oleg Epstein、Marian C. Bryan、Alan C. Cheng、Katayoun Derakhchan、Thomas A. Dineen、Dean Hickman、Zihao Hua、Jason B. Human、Charles Kreiman、Isaac E. Marx、Matthew M. Weiss、Robert C. Wahl、Paul H. Wen、Douglas A. Whittington、Stephen Wood、Xiao Mei Zheng、Robert T. Fremeau、Ryan D. White、Vinod F. Patel

  DOI：10.1021/jm501266w

  日期：2014.12.11

  The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust A beta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust A beta reduction in a rat pharmacodynamic model (78% A beta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.