4-(pyridin-4-yl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide

• 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: 4-(pyridin-4-yl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide
• 英文别名: 4-pyridin-4-yl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide
• 化学式: C₁₇H₁₇F₃N₄O
• 分子量: 350.343
• InChiKey: ALLYCDOJKGMNIP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  48.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(4-吡啶基)哌嗪 、 4-三氟甲基苯基异氰酸酯 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 4-(pyridin-4-yl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide
  参考文献：
  名称：

  Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma

  摘要：

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is extremely refractory to the therapeutic approaches that have been evaluated to date. Recently, it has been demonstrated that PDAC tumors are dependent upon a metabolic pathway involving aspartate aminotransferase 1, also known as glutamate-oxaloacetate transaminase 1 (GOT1), for the maintenance of redox homeostasis and sustained proliferation. As such, small molecule inhibitors targeting this metabolic pathway may provide a novel therapeutic approach for the treatment of this devastating disease. To this end, from a high throughput screen of similar to 800,000 molecules, 4-(1H-indol-4-yl)-N-phenylpiperazine-1-carboxamide was identified as an inhibitor of GOT1. Mouse pharmacokinetic studies revealed that potency, rather than inherent metabolic instability, would limit immediate cell- and rodent xenograft-based experiments aimed at validating this potential cancer metabolism-related target. Medicinal chemistry-based optimization resulted in the identification of multiple derivatives with >10-fold improvements in potency, as well as the identification of a tryptamine-based series of GOT1 inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2018.04.061

文献信息

• Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma
  作者：Justin Anglin、Reza Beheshti Zavareh、Philipp N. Sander、Daniel Haldar、Edouard Mullarky、Lewis C. Cantley、Alec C. Kimmelman、Costas A. Lyssiotis、Luke L. Lairson

  DOI：10.1016/j.bmcl.2018.04.061

  日期：2018.9

  Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is extremely refractory to the therapeutic approaches that have been evaluated to date. Recently, it has been demonstrated that PDAC tumors are dependent upon a metabolic pathway involving aspartate aminotransferase 1, also known as glutamate-oxaloacetate transaminase 1 (GOT1), for the maintenance of redox homeostasis and sustained proliferation. As such, small molecule inhibitors targeting this metabolic pathway may provide a novel therapeutic approach for the treatment of this devastating disease. To this end, from a high throughput screen of similar to 800,000 molecules, 4-(1H-indol-4-yl)-N-phenylpiperazine-1-carboxamide was identified as an inhibitor of GOT1. Mouse pharmacokinetic studies revealed that potency, rather than inherent metabolic instability, would limit immediate cell- and rodent xenograft-based experiments aimed at validating this potential cancer metabolism-related target. Medicinal chemistry-based optimization resulted in the identification of multiple derivatives with >10-fold improvements in potency, as well as the identification of a tryptamine-based series of GOT1 inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.