tert-butyl N-[(2R)-1-(5-bromopyridin-3-yl)oxy-3-[tert-butyl(dimethyl)silyl]oxypropan-2-yl]carbamate | 552332-00-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl N-[(2R)-1-(5-bromopyridin-3-yl)oxy-3-[tert-butyl(dimethyl)silyl]oxypropan-2-yl]carbamate
• CAS: 552332-00-0
• 化学式: C₁₉H₃₃BrN₂O₄Si
• 分子量: 461.472
• InChiKey: YPWZKKBHXSVWLT-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.14
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  69.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[(2R)-1-(5-bromopyridin-3-yl)oxy-3-[tert-butyl(dimethyl)silyl]oxypropan-2-yl]carbamate 在 tris(dibenzylideneacetone)dipalladium (0) 、 三(邻甲基苯基)磷 四丁基氟化铵 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 5-[5-((2S)-1-tert-butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methylindazole-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019
• 作为产物：
  描述：

  3-溴-5-羟基吡啶 、 (R)-(+)-N-(叔丁氧基羰基)-O-(叔丁基二甲基甲硅烷基)丝氨酸醇 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 以99%的产率得到tert-butyl N-[(2R)-1-(5-bromopyridin-3-yl)oxy-3-[tert-butyl(dimethyl)silyl]oxypropan-2-yl]carbamate
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019