(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 | 882169-91-7

• 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
• 中文名称: (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
• 英文名称: (S)-[2-(5-bromopyridin-3-yloxy)-1-(1H-indol-3-ylmethyl)ethyl]carbamic acid tert-butyl ester
• 英文别名: tert-butyl (1S)-2-[(5-hydroxypyridin-3-yl)oxy]-1-(1H-indol-3-ylmethyl)ethylcarbamate；(S)-tert-butyl 1-(5-bromopyridin-3-yloxy)-3-(1H-indol-3-yl)propan-2-ylcarbamate；tert-butyl N-[(2S)-1-(5-bromopyridin-3-yl)oxy-3-(1H-indol-3-yl)propan-2-yl]carbamate
• CAS: 882169-91-7
• 化学式: C₂₁H₂₄BrN₃O₃
• 分子量: 446.344
• InChiKey: LIKXKTWTVNLBOR-INIZCTEOSA-N

物化性质

• 沸点：
  627.5±55.0 °C(Predicted)
• 密度：
  1.376±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 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-(5-溴吡啶-3-基氧基)-3-(1H-吲哚-3-基)丙烷-2-氨基甲酸叔丁酯 在 palladium diacetate 、 三(邻甲基苯基)磷 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 8.0h， 生成 ((S)-1-(1H-Indol-3-ylmethyl)-2-{5-[(E)-2-(2-indol-1-yl-pyridin-4-yl)-vinyl]-pyridin-3-yloxy}-ethyl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Discovery of trans-3,4′-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation

  摘要：

  A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC50 values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined. (C) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.12.017
• 作为产物：
  描述：

  3-溴-5-羟基吡啶 、 N-α-(叔丁氧基羰基)-L-色氨醇 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79%的产率得到(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
  参考文献：
  名称：

  吲唑-吡啶基蛋白激酶B / Akt抑制剂的合成和SAR。

  摘要：

  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。

  DOI：

  10.1016/j.bmc.2006.06.047

文献信息

• Kinase inhibitors
  申请人：——

  公开号：US20030199511A1

  公开（公告）日：2003-10-23

  Compounds having the formula 1 are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.

  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。
• 一种是ATP竞争性小分子AKT抑制剂 A443654的合成方法
  申请人：上海皓元生物医药科技有限公司

  公开号：CN104610229B

  公开（公告）日：2017-01-18

  本发明公开了一种ATP竞争性小分子AKT抑制剂A443654的合成方法，该方法以化合物1为起始原料，经过氨基保护、Suzuki反应、保护基脱除得到化合物6（A‑443654）。该方法避免了剧毒试剂六甲基二锡的使用，安全性好、对环境友好，并且缩短了反应时间、反应收率高、降低了工艺成本、适合工业化大规模生产。
• Isoquinoline–pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity
  作者：Gui-Dong Zhu、Jianchun Gong、Akiyo Claiborne、Keith W. Woods、Viraj B. Gandhi、Sheela Thomas、Yan Luo、Xuesong Liu、Yan Shi、Ran Guan、Shayna R. Magnone、Vered Klinghofer、Eric F. Johnson、Jennifer Bouska、Alexander Shoemaker、Anatol Oleksijew、Vincent S. Stoll、Ron De Jong、Tilman Oltersdorf、Qun Li、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1016/j.bmcl.2006.03.041

  日期：2006.6

  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.
• Synthesis and structure–activity relationship of 3,4′-bispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer
  作者：Qun Li、Keith W. Woods、Sheela Thomas、Gui-Dong Zhu、Garrick Packard、John Fisher、Tongmei Li、Jianchun Gong、Jurgen Dinges、Xiaohong Song、Jason Abrams、Yan Luo、Eric F. Johnson、Yan Shi、Xuesong Liu、Vered Klinghofer、Ron Des Jong、Tilman Oltersdorf、Vincent S. Stoll、Clarissa G. Jakob、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1016/j.bmcl.2005.12.065

  日期：2006.4

  Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC50 of 1.3 nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC50 values of 0.42 and 0.59 mu M against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC50 of 1.5 mu M. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined. (C) 2005 Elsevier Ltd. All rights reserved.
• 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。