1-(3,4-difluorobenzyl)-2-oxo-N-(2-oxoindolin-5-yl)-1,2-dihydropyridine-3-carboxamide

• 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: 1-(3,4-difluorobenzyl)-2-oxo-N-(2-oxoindolin-5-yl)-1,2-dihydropyridine-3-carboxamide
• 英文别名: 1-[(3,4-difluorophenyl)methyl]-2-oxo-N-(2-oxo-1,3-dihydroindol-5-yl)pyridine-3-carboxamide
• 化学式: C₂₁H₁₅F₂N₃O₃
• 分子量: 395.365
• InChiKey: QPAYENROBZKJBD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  78.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(3,4-difluorobenzyl)-2-oxo-N-(2-oxoindolin-5-yl)-1,2-dihydropyridine-3-carboxamide 、 1-甲基-1H-咪唑-2-甲醛 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 4.0h， 以32%的产率得到(E)-1-(3,4-difluorobenzyl)-N-(3-((1-methyl-1H-imidazol-2-yl)methylene)-2-oxoindolin-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide
  参考文献：
  名称：

  Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma

  摘要：

  The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the "master kinase" of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds were synthesised and a tandem application of docking and Molecular Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower IC50 (IC50 = 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.04.003
• 作为产物：
  描述：

  2-羟基烟酸 在 sodium hydride 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 30.0h， 生成 1-(3,4-difluorobenzyl)-2-oxo-N-(2-oxoindolin-5-yl)-1,2-dihydropyridine-3-carboxamide
  参考文献：
  名称：

  [EN] 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS INHIBITORS OF PDK1
  [FR] COMPOSÉS DE 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE ET LEUR UTILISATION À TITRE D'INHIBITEURS DE PDK1

  摘要：

  本发明涉及一种式（I）的2-氧代-1,2-二氢吡啶-3-羧酰胺化合物，以及式（II）的新型2-氧代-1,2-二氢吡啶-3-羧酰胺化合物，在需要PDK1酶抑制剂的病理学治疗中，如糖尿病、阿尔茨海默病和朊病等神经退行性疾病，以及乳腺癌、胰腺癌和胶质母细胞瘤等肿瘤，特别是胶质母细胞瘤。

  公开号：

  WO2016198597A1

文献信息

• [EN] 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS INHIBITORS OF PDK1<br/>[FR] COMPOSÉS DE 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE ET LEUR UTILISATION À TITRE D'INHIBITEURS DE PDK1
  申请人：INT SOC FOR DRUG DEV S R L

  公开号：WO2016198597A1

  公开（公告）日：2016-12-15

  The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) and new 2-oxo-1,2-dihydropyridine-3-carboxamide compounds of Formula (II) in the treatment of pathologies which require an inhibitor of PDK1 enzyme such as diabetes, neurodegenerative diseases such as Alzheimer's and Prion Diseases, and tumours such as breast, and pancreatic cancers and glioblastoma, particularly glioblastoma.

  本发明涉及一种式（I）的2-氧代-1,2-二氢吡啶-3-羧酰胺化合物，以及式（II）的新型2-氧代-1,2-二氢吡啶-3-羧酰胺化合物，在需要PDK1酶抑制剂的病理学治疗中，如糖尿病、阿尔茨海默病和朊病等神经退行性疾病，以及乳腺癌、胰腺癌和胶质母细胞瘤等肿瘤，特别是胶质母细胞瘤。
• 2-oxo-1,2-dihydropyridine-3-carboxamide compounds and their use as inhibitors of PDK1
  申请人：INTERNATIONAL SOCIETY FOR DRUG DEVELOPMENT S.R.L.

  公开号：US10351548B2

  公开（公告）日：2019-07-16

  The present invention concern a 2-oxo-1,2-dihydropyridine-3-carboxamide compound of Formula (I) and new 2-oxo-1,2-dihydropyridine-3-carboxamide compounds of Formula (II) in the treatment of pathologies which require an inhibitor of PDK1 enzyme such as diabetes, neurodegenerative diseases such as Alzheimer's and Prion Diseases, and tumors such as breast, and pancreatic cancers and glioblastoma, particularly glioblastoma.

  本发明涉及一种式（I）的 2-氧代-1,2-二氢吡啶-3-甲酰胺化合物和新的式（II）的 2-氧代-1,2-二氢吡啶-3-甲酰胺化合物，用于治疗需要 PDK1 酶抑制剂的病症，如糖尿病、神经退行性疾病，如阿尔茨海默病和朊病毒病，以及肿瘤，如乳腺癌、胰腺癌和胶质母细胞瘤，特别是胶质母细胞瘤。
• 2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE COMPOUNDS AND THEIR USE AS INHIBITORS OF PDK1
  申请人：International Society for Drug Development S.r.l.

  公开号：EP3307726A1

  公开（公告）日：2018-04-18
• Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma
  作者：Simona Sestito、Simona Daniele、Giulia Nesi、Elisa Zappelli、Danilo Di Maio、Luciana Marinelli、Maria Digiacomo、Annalina Lapucci、Claudia Martini、Ettore Novellino、Simona Rapposelli

  DOI：10.1016/j.ejmech.2016.04.003

  日期：2016.8

  The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt pathway. Also named the "master kinase" of the AGC family, PDK1 plays a critical role in tumorigenesis, by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation. Although there have been done huge efforts in discovering specific compounds targeting PDK1, nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1 inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds were synthesised and a tandem application of docking and Molecular Dynamic (MD) was employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower IC50 (IC50 = 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1 inhibitors and encourage us to further studies in this direction. (C) 2016 Elsevier Masson SAS. All rights reserved.