N8-(cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimidino[5,4-d]pyrimidine-4,8-diamine | 1303469-70-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N8-(cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimidino[5,4-d]pyrimidine-4,8-diamine
• 英文别名: N8-(cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine；Khk-IN-1；8-N-(cyclopropylmethyl)-4-N-(2-methylsulfanylphenyl)-2-piperazin-1-ylpyrimido[5,4-d]pyrimidine-4,8-diamine
• CAS: 1303469-70-6
• 化学式: C₂₁H₂₆N₈S
• 分子量: 422.557
• InChiKey: HFLMLZKGLUEWBU-UHFFFAOYSA-N

物化性质

• 沸点：
  646.4±65.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N8-(cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimidino[5,4-d]pyrimidine-4,8-diamine 在 盐酸 作用下， 以 甲醇 、 乙醚 为溶剂， 以380 mg的产率得到KHK-IN-1 hydrochloride
  参考文献：
  名称：

  酮己糖激酶抑制剂：发现具有补充 ATP 结合位点的特定取代基的嘧啶并嘧啶

  摘要：

  通过抑制酮己糖激酶（KHK；果糖激酶）来减弱果糖代谢应该可以降低体重、游离脂肪酸和甘油三酯，从而提供一种新的方法来治疗糖尿病和肥胖症以应对现代饮食。我们已经在一系列嘧啶并嘧啶 ( 1 ) 中鉴定了人肝 KHK 的强效选择性抑制剂。例如，8，38，和47个显示出KHK IC 50个12，7和8纳米的值，分别与也显示了强的蜂窝KHK抑制（IC 50 <500纳米），其涉及它们的固有效力VS KHK及其穿透细胞的能力。3 , 8 KHK配合物的X射线共晶结构和47揭示了酶的腺苷 5'-三磷酸 (ATP) 结合口袋内的重要相互作用。

  DOI：

  10.1021/ml200070g
• 作为产物：
  描述：

  在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 N8-(cyclopropylmethyl)-N4-(2-(methylthio)phenyl)-2-(piperazin-1-yl)pyrimidino[5,4-d]pyrimidine-4,8-diamine
  参考文献：
  名称：

  Pyrimidinopyrimidine inhibitors of ketohexokinase: Exploring the ring C2 group that interacts with Asp-27B in the ligand binding pocket

  摘要：

  Inhibitors of ketohexokinase (KHK) have potential for the treatment of diabetes and obesity. We have continued studies on a pyrimidinopyrimidine series of potent KHK inhibitors by exploring the 2-position substituent (R-3) that interacts with Asp-27B in the ATP-binding region of KHK (viz. 1, 2; Table 1). We found that increased spacing between the terminal ammonium group and the heterocyclic scaffold (viz. 16-20), such that interaction with Asp-27B is not possible, still results in potent KHK inhibition (IC50 = 15-50 nM). We propose a new interaction with Asp-194, which serves to expand the pyrimidinopyrimidine pharmacophore. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.06.008

文献信息

• SUBSTITUTED 3-AZABICYCLO[3.1.0]HEXANES AS KETOHEXOKINASE INHIBITORS
  申请人：Pfizer Inc.

  公开号：US20170183328A1

  公开（公告）日：2017-06-29

  Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

  本文提供了替代3-氮杂双环[3.1.0]己烷作为酮己糖激酶抑制剂，制备该类化合物的方法，以及包括向需要的哺乳动物施用该类化合物的方法。
• Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors
  申请人：Pfizer Inc.

  公开号：US10174007B2

  公开（公告）日：2019-01-08

  Provided herein are substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors, processes to make said compounds, and methods comprising administering said compounds to a mammal in need thereof.

  本文提供了作为酮六磷酸酶抑制剂的取代 3-氮杂双环[3.1.0]己烷、制造所述化合物的工艺，以及将所述化合物施用给需要的哺乳动物的方法。
• COMPOSITIONS AND METHODS FOR TARGETING FRUCTOSE ENZYMES AND TRANSPORTERS FOR THE TREATMENT OF CANCER
  申请人：Duke University

  公开号：US20190231761A1

  公开（公告）日：2019-08-01

  The disclosure relates to compositions and methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a therapeutic agent capable of down-regulating and/or inhibiting a fructose enzyme or fructose transporter in a cell of the subject such that the cancer growth is suppressed.
• ANTI-FRUCTOSE THERAPY FOR COLORECTAL AND SMALL INTESTINE CANCERS
  申请人：Cornell University

  公开号：US20220400732A1

  公开（公告）日：2022-12-22

  As described herein ingestion of high amounts of sugar, especially fructose, can increase the growth of intestinal tumors. Such cancer growth can be inhibited or prevented by limiting the amounts of sugar and amino acids ingested, by inhibiting ketohexokinase (KHK), fructose transport (via GLUT5), fatty acid synthesis (via FASN), phosphoinositide 3-kinases (PI3K), or by limiting amounts of sugar and amino acids ingested while also receiving KHK inhibitors, GLUT5 inhibitors, FASN inhibitors, PI3K inhibitors, or a combination of such inhibitors.
• US9809579B2
  申请人：——

  公开号：US9809579B2

  公开（公告）日：2017-11-07