(2S)-3-[(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)amino]-1,2-propanediol | 1052112-79-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并吡啶类
• 英文名称: (2S)-3-[(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)amino]-1,2-propanediol
• 英文别名: (2S)-3-[(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)amino]propane-1,2-diol；(2S)-3-[3-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methylbut-1-ynyl)imidazo[4,5-c]pyridin-7-yl]oxypropylamino]propane-1,2-diol
• CAS: 1052112-79-4
• 化学式: C₂₁H₂₉N₇O₅
• 分子量: 459.505
• InChiKey: XMRDIROQMJMYRD-ZDUSSCGKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  33
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  178
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  (2S)-3-[(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)amino]-1,2-propanediol 、 2-甲基-3-丁炔-2-醇 在 四(三苯基膦)钯 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 sodium iodide 、 锌 作用下， 以 二甲基亚砜 为溶剂， 反应 3.0h， 以60%的产率得到(2S)-3-[(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-4-(3-hydroxy-3-methyl-1-butyn-1-yl)-1H-imidazo[4,5-c]pyridin-7-yl]oxy}propyl)amino]-1,2-propanediol
  参考文献：
  名称：

  Identification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT Kinase

  摘要：

  Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.

  DOI：

  10.1021/jm8004527

文献信息

• Identification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3<i>S</i>)-3-piperidinylmethyl]oxy}-1<i>H</i>-imidazo[4,5-<i>c</i>]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT Kinase
  作者：Dirk A. Heerding、Nelson Rhodes、Jack D. Leber、Tammy J. Clark、Richard M. Keenan、Louis V. Lafrance、Mei Li、Igor G. Safonov、Dennis T. Takata、Joseph W. Venslavsky、Dennis S. Yamashita、Anthony E. Choudhry、Robert A. Copeland、Zhihong Lai、Michael D. Schaber、Peter J. Tummino、Susan L. Strum、Edgar R. Wood、Derek R. Duckett、Derek Eberwein、Victoria B. Knick、Timothy J. Lansing、Randy T. McConnell、ShuYun Zhang、Elisabeth A. Minthorn、Nestor O. Concha、Gregory L. Warren、Rakesh Kumar

  DOI：10.1021/jm8004527

  日期：2008.9.25

  Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.