5-chloro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 5-chloro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide
• 英文别名: 5-chloro-N-hexyl-2,4-dioxopyrimidine-1-carboxamide
• 化学式: C₁₁H₁₆ClN₃O₃
• 分子量: 273.719
• InChiKey: MVWIGWIKOQYGRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.33
• 重原子数：
  18.0
• 可旋转键数：
  5.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  83.96
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  5-chloro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide 、 氯甲酸异丁酯 以to afford the title compound (0.047 g, 29%) as a white solid的产率得到isobutyl 5-chloro-3-(hexylcarbamoyl)-2,6-dioxopyrimidine-1-carboxylate
  参考文献：
  名称：

  Acid ceramidase inhibitors and their use as medicaments

  摘要：

  本发明涉及第一方面的I式化合物，其定义如下，其药学上可接受的盐以及含有这种化合物的药物组合物。本发明还涉及I式化合物的用途，作为酸性酯胺酶抑制剂，并用于治疗癌症和其他调节酯胺水平具有临床意义的疾病。

  公开号：

  US09428465B2
• 作为产物：
  描述：

  5-氯尿嘧啶 、 异氰酸己酯 在 吡啶 、 4-二甲氨基吡啶 作用下， 生成 5-chloro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide
  参考文献：
  名称：

  通过卡莫氟结构引导的命中到先导优化发现抗病毒 SARS-CoV-2 主要蛋白酶抑制剂

  摘要：

  严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 主要蛋白酶 (M pro ) 已成为开发针对 COVID-19 感染的抗 SARS-CoV-2 药物的目标，因为 M pro处理必需的病毒多蛋白并发挥关键作用在 SARS-CoV-2 复制中的作用。在这项研究中，我们报告了源自卡莫氟的新型 SARS-CoV-2 M pro抑制剂的开发，卡莫氟是一种先前鉴定的化合物，作为 SARS-CoV-2 M pro的共价抑制剂显示出中等效力。为了采用结构引导的药物设计策略，首先通过对接模拟预测了卡莫氟在 M pro催化活性位点上的假定完整结合模式。基于预测的结合模式，对一系列旨在占据M pro底物结合区域的卡莫氟衍生物进行了构效关系分析。结果， 发现了一种基于吲哚的衍生物，推测与 S4 结合袋相互作用， 21b (IC 50 = 1.5 ± 0.1 μM)。通过结合对接模拟、自由能扰动计算和子口

  DOI：

  10.1016/j.ejmech.2023.115720

文献信息

• ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS
  申请人：FONDAZIONE ISTITUTO ITALIANO DI TECHNOLOGIA

  公开号：US20150111892A1

  公开（公告）日：2015-04-23

  The present invention concerns, in a first aspect, compounds of Formula I as defined herein, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing such compounds. The present invention also relates to compounds of Formula I for use as acid ceramidase inhibitors, and in the treatment of cancer and other disorders in which modulation of the levels of ceramide is clinically relevant.

  本发明涉及第一方面的I式化合物，其定义如本文所述，其药用盐以及含有这种化合物的药物组合物。本发明还涉及I式化合物的用途，用作酸酶抑制剂，以及在癌症和其他需要临床相关的调节酸酶水平的疾病治疗中的用途。
• [EN] ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS<br/>[FR] INHIBITEURS DE LA CÉRAMIDASE ACIDE ET LEUR UTILISATION COMME MÉDICAMENTS
  申请人：FOND ISTITUTO ITALIANO DI TECNOLOGIA

  公开号：WO2013178576A1

  公开（公告）日：2013-12-05

  The present invention concerns, in a first aspect, compounds of Formula I as defined herein, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing such compounds. The present invention also relates to compounds of Formula I for use as acid ceramidase inhibitors, and in the treatment of cancer and other disorders in which modulation of the levels of ceramide is clinically relevant.

  本发明涉及第一方面的Formula I化合物，其定义如下，以及其药用盐和含有这种化合物的药物组合物。本发明还涉及Formula I化合物作为酸酶抑制剂的用途，以及在治疗癌症和其他需要临床上调节酸酶水平的疾病中的应用。
• Acid ceramidase inhibitors and their use as medicaments
  申请人：FONDAZIONE ISTITUTO ITALIANO DI TECHNOLOGIA

  公开号：US09428465B2

  公开（公告）日：2016-08-30

  The present invention concerns, in a first aspect, compounds of Formula I as defined herein, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing such compounds. The present invention also relates to compounds of Formula I for use as acid ceramidase inhibitors, and in the treatment of cancer and other disorders in which modulation of the levels of ceramide is clinically relevant.

  本发明涉及第一方面的I式化合物，其定义如下，其药学上可接受的盐以及含有这种化合物的药物组合物。本发明还涉及I式化合物的用途，作为酸性酯胺酶抑制剂，并用于治疗癌症和其他调节酯胺水平具有临床意义的疾病。
• US9428465B2
  申请人：——

  公开号：US9428465B2

  公开（公告）日：2016-08-30
• Acid Ceramidase in Melanoma
  作者：Natalia Realini、Francesca Palese、Daniela Pizzirani、Silvia Pontis、Abdul Basit、Anders Bach、Anand Ganesan、Daniele Piomelli

  DOI：10.1074/jbc.m115.666909

  日期：2016.1

  Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphingolipid signaling in melanoma. We found that AC expression is markedly elevated in normal human melanocytes and proliferative melanoma cell lines, compared with other skin cells (keratinocytes and fibroblasts) and non-melanoma cancer cells. High AC expression was also observed in biopsies from human subjects with Stage II melanoma. Immunofluorescence studies revealed that the subcellular localization of AC differs between melanocytes (where it is found in both cytosol and nucleus) and melanoma cells (where it is primarily localized to cytosol). In addition to having high AC levels, melanoma cells generate lower amounts of ceramides than normal melanocytes do. This down-regulation in ceramide production appears to result from suppression of the de novo biosynthesis pathway. To test whether AC might contribute to melanoma cell proliferation, we blocked AC activity using a new potent (IC50 = 12 nM) and stable inhibitor. AC inhibition increased cellular ceramide levels, decreased sphingosine 1-phosphate levels, and acted synergistically with several, albeit not all, antitumoral agents. The results suggest that AC-controlled sphingolipid metabolism may play an important role in the control of melanoma proliferation.