5-{5-[(2S)-2-tert-Butoxycarbonylamino-3-(3-trifluoromethoxy-phenyl)-propoxy]-pyridin-3-yl}-3-methyl-indazole-1-carboxylic acid tert-butyl Ester | 552332-05-5

• 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: 5-{5-[(2S)-2-tert-Butoxycarbonylamino-3-(3-trifluoromethoxy-phenyl)-propoxy]-pyridin-3-yl}-3-methyl-indazole-1-carboxylic acid tert-butyl Ester
• 英文别名: tert-butyl 3-methyl-5-[5-[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[3-(trifluoromethoxy)phenyl]propoxy]pyridin-3-yl]indazole-1-carboxylate
• CAS: 552332-05-5
• 化学式: C₃₃H₃₇F₃N₄O₆
• 分子量: 642.675
• InChiKey: MXRNFXMBNLFPSU-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  5-{5-[(2S)-2-tert-Butoxycarbonylamino-3-(3-trifluoromethoxy-phenyl)-propoxy]-pyridin-3-yl}-3-methyl-indazole-1-carboxylic acid tert-butyl Ester 、 三氟乙酸 以 二氯甲烷 为溶剂， 生成 (2S)-1-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxy-3-[3-(trifluoromethoxy)phenyl]propan-2-amine;2,2,2-trifluoroacetic acid
  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：

  (R)-(+)-N-(叔丁氧基羰基)-O-(叔丁基二甲基甲硅烷基)丝氨酸醇 在 tris(dibenzylideneacetone)dipalladium (0) 、 copper(I) bromide dimethylsulfide complex 、 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 5.67h， 生成 5-{5-[(2S)-2-tert-Butoxycarbonylamino-3-(3-trifluoromethoxy-phenyl)-propoxy]-pyridin-3-yl}-3-methyl-indazole-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

文献信息

• Kinase inhibitors
  申请人：——

  公开号：US20030187026A1

  公开（公告）日：2003-10-02

  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。
• US6831175B2
  申请人：——

  公开号：US6831175B2

  公开（公告）日：2004-12-14
• Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension
  作者：Gui-Dong Zhu、Viraj B. Gandhi、Jianchun Gong、Sheela Thomas、Keith W. Woods、Xiaohong Song、Tongmei Li、R. Bruce Diebold、Yan Luo、Xuesong Liu、Ran Guan、Vered Klinghofer、Eric F. Johnson、Jennifer Bouska、Amanda Olson、Kennan C. Marsh、Vincent S. Stoll、Mulugeta Mamo、James Polakowski、Thomas J. Campbell、Ruth L. Martin、Gary A. Gintant、Thomas D. Penning、Qun Li、Saul H. Rosenberg、Vincent L. Giranda

  DOI：10.1021/jm0701019

  日期：2007.6.1

  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.