(S)-[1-(1H-indol-3-ylmethyl)-2-(5-trimethylstannylpyridin-3-yloxy)ethyl]carbamic acid tert-butyl ester | 900517-08-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (S)-[1-(1H-indol-3-ylmethyl)-2-(5-trimethylstannylpyridin-3-yloxy)ethyl]carbamic acid tert-butyl ester
• 英文别名: tert-butyl (1S)-2-(1H-indol-3-yl)-1-({[5-(trimethylstannyl)pyridin-3-yl]oxy}methyl)ethylcarbamate；tert-Butyl (S)-1-(5-(trimethylstannyl)pyridin-3-yloxy)-3-(1H-indol-3-yl)propan-2-ylcarbamate；tert-butyl N-[(2S)-1-(1H-indol-3-yl)-3-(5-trimethylstannylpyridin-3-yl)oxypropan-2-yl]carbamate
• CAS: 900517-08-0
• 化学式: C₂₄H₃₃N₃O₃Sn
• 分子量: 530.254
• InChiKey: MBCHKIUXKZAJSN-FXAGWRDUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.62
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  76.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-[1-(1H-indol-3-ylmethyl)-2-(5-trimethylstannylpyridin-3-yloxy)ethyl]carbamic acid tert-butyl ester 在 四(三苯基膦)钯 、 tris(dibenzylideneacetone)dipalladium (0) 、 三(邻甲基苯基)磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 [(S)-1-[5-(3-Cyano-isoquinolin-6-yl)-pyridin-3-yloxymethyl]-2-(1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Isoquinoline–pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity

  摘要：

  The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse iv t(1/2) = 0.3 h, po F= 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (iv t(1/2) = 5.0 h, po F = 51%) but resulted in > 500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.03.041
• 作为产物：
  描述：

  (S)-1-(5-溴吡啶-3-基氧基)-3-(1H-吲哚-3-基)丙烷-2-氨基甲酸叔丁酯 、 六甲基二锡 在 四(三苯基膦)钯 作用下， 以 2,4-滴二甲胺盐 为溶剂， 反应 36.0h， 以34%的产率得到(S)-[1-(1H-indol-3-ylmethyl)-2-(5-trimethylstannylpyridin-3-yloxy)ethyl]carbamic acid tert-butyl ester
  参考文献：
  名称：

  Kinase inhibitors

  摘要：

  具有以下化学式的化合物对抑制蛋白激酶很有用。还公开了抑制蛋白激酶的组合物以及在患者中抑制蛋白激酶的方法。

  公开号：

  US20030199511A1

文献信息

• Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors
  作者：Keith W. Woods、John P. Fischer、Akiyo Claiborne、Tongmei Li、Sheela A. Thomas、Gui-Dong Zhu、Robert B. Diebold、Xuesong Liu、Yan Shi、Vered Klinghofer、Edward K. Han、Ran Guan、Shayna R. Magnone、Eric F. Johnson、Jennifer J. Bouska、Amanda M. Olson、Ron de Jong、Tilman Oltersdorf、Yan Luo、Saul H. Rosenberg、Vincent L. Giranda、Qun Li

  DOI：10.1016/j.bmc.2006.06.047

  日期：2006.10

  A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K(i)=0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue

  报道了一系列含杂芳基吡啶的Akt抑制剂。讨论了合成和结构-活性之间的关系，从而发现了吲唑-吡啶类似物（K（i）= 0.16 nM）。这些化合物在ATP结合位点结合，是有效的，ATP竞争性的和可逆的Akt活性抑制剂。没有观察到该类似物在Akt同工型中的选择性，但是对一组其他激酶具有良好的选择性。它对AGC激酶家族的其他成员的选择性最低，但是对Akt的选择性是PKA的40倍。该化合物显示出细胞活性，并显着减慢了体内肿瘤的生长。
• Design and synthesis of pyridine–pyrazolopyridine-based inhibitors of protein kinase B/Akt
  作者：Gui-Dong Zhu、Jianchun Gong、Viraj B. Gandhi、Keith Woods、Yan Luo、Xuesong Liu、Ran Guan、Vered Klinghofer、Eric F. Johnson、Vincent S. Stoll、Mulugeta Mamo、Qun Li、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1016/j.bmc.2007.01.010

  日期：2007.3

  Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed. (c) 2007 Elsevier Ltd. All rights reserved.
• Discovery and SAR of oxindole–pyridine-based protein kinase B/Akt inhibitors for treating cancers
  作者：Gui-Dong Zhu、Viraj B. Gandhi、Jianchun Gong、Yan Luo、Xuesong Liu、Yan Shi、Ran Guan、Shayna R. Magnone、Vered Klinghofer、Eric F. Johnson、Jennifer Bouska、Alexander Shoemaker、Anatol Oleksijew、Ken Jarvis、Chang Park、Ron De Jong、Tilman Oltersdorf、Qun Li、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1016/j.bmcl.2006.04.005

  日期：2006.7

  We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC(50) of 0.17nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (11k) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity.