N-[(2S,3R)-1-(3,5-difluorophenyl)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide | 939441-82-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[(2S,3R)-1-(3,5-difluorophenyl)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide
• CAS: 939441-82-4
• 化学式: C₂₈H₃₇F₂N₃O₃
• 分子量: 501.617
• InChiKey: ZZIYYUNIVIIWAU-CCDWMCETSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  83.5
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氟-5-溴吡啶 在 2,2,6,6-四甲基哌啶 、 盐酸 、 正丁基锂 、 三乙酰氧基硼氢化钠 、 N,N-二异丙基乙胺 、 cesium fluoride 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 16.0h， 生成 N-[(2S,3R)-1-(3,5-difluorophenyl)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide
  参考文献：
  名称：

  A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase

  摘要：

  beta-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against beta-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A beta(40) levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

  DOI：

  10.1021/ml3000148

文献信息

• A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase
  作者：Matthew R. Kaller、Scott S. Harried、Brian Albrecht、Patricia Amarante、Safura Babu-Khan、Michael D. Bartberger、James Brown、Ryan Brown、Kui Chen、Yuan Cheng、Martin Citron、Michael D. Croghan、Russell Graceffa、Dean Hickman、Ted Judd、Chuck Kriemen、Daniel La、Vivian Li、Patricia Lopez、Yi Luo、Craig Masse、Holger Monenschein、Thomas Nguyen、Lewis D. Pennington、Tisha San Miguel、E. Allen Sickmier、Robert C. Wahl、Matthew M. Weiss、Paul H. Wen、Toni Williamson、Stephen Wood、May Xue、Bryant Yang、Jianhua Zhang、Vinod Patel、Wenge Zhong、Stephen Hitchcock

  DOI：10.1021/ml3000148

  日期：2012.11.8

  beta-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against beta-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A beta(40) levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.