N-[cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-2-nitrobenzamide

• 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: N-[cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-2-nitrobenzamide
• 英文别名: N-[2-(cyclohexylamino)-1-(4-nitrophenyl)-2-oxoethyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-2-nitrobenzamide
• 化学式: C₃₂H₃₆N₄O₉
• 分子量: 620.659
• InChiKey: KTCYOHGOMNAEBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  45
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  169
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  异氰环已烷 、 5-甲氧基-2-硝基苯甲酸 、 对硝基苯甲醛 、 3,4-二甲氧基苯乙胺 以 甲醇 为溶剂， 以99%的产率得到N-[cyclohexylcarbamoyl-(4-nitrophenyl)methyl]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-2-nitrobenzamide
  参考文献：
  名称：

  Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections

  摘要：

  Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct acting antivirals (DAAs), including inhibitors Of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening; the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed Selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics.

  DOI：

  10.1021/acs.jmedchem.5b01064

文献信息

• Bis-amide derivative and use thereof
  申请人：University-Industry Cooperation Group of Kyung Hee University

  公开号：US10064843B2

  公开（公告）日：2018-09-04

  The present invention relates to a novel bis-amide derivative compound or a pharmaceutically acceptable salt thereof; a method of preparation thereof; and a pharmaceutical composition for preventing or treating diseases caused by hepatitis C virus infection and health functional food for preventing or ameliorating diseases caused by hepatitis C virus infection, containing the bis-amide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient. The novel bis-amide derivative compound of the present invention, particularly WJCPA-126, specifically binds to the catalytic site of CypA to effectively inhibit the activity of an isomerase, and the duration of the inhibitory effect can be increased because WJCPA-126 binds to CypA with high binding affinity exhibiting a low dissociation rate (Koff). Accordingly, WJCPA-126 has nontoxic and non-immunosuppressive characteristics and can effectively inhibit HCV replication in vitro and in vivo model systems. Additionally, WJCPA-126 reactivates the host interferon response through an increase in the expression of IFN-stimulated genes (ISGs) and the inhibition of interleukin-8 (IL-8) secretion. Therefore, a series of the bis-amide derivatives including WJCPA-126 can be useful as a novel type CypA inhibitor exhibiting antiviral effect.

  本发明涉及一种新型双酰胺衍生物化合物或其药学上可接受的盐；其制备方法；以及一种预防或治疗丙型肝炎病毒感染所致疾病的药物组合物和预防或改善丙型肝炎病毒感染所致疾病的保健功能食品，其活性成分中含有该双酰胺衍生物化合物或其药学上可接受的盐。 本发明的新型双酰胺衍生物化合物，特别是 WJCPA-126，能与 CypA 的催化位点特异性结合，有效抑制异构酶的活性，而且由于 WJCPA-126 与 CypA 的结合亲和力高，解离率（Koff）低，因此能延长抑制作用的持续时间。因此，WJCPA-126 具有无毒、无免疫抑制的特点，可在体外和体内模型系统中有效抑制 HCV 复制。此外，WJCPA-126 还能通过增加 IFN 刺激基因（ISGs）的表达和抑制白细胞介素-8（IL-8）的分泌来重新激活宿主的干扰素反应。因此，包括 WJCPA-126 在内的一系列双酰胺衍生物可作为一种新型 CypA 抑制剂发挥抗病毒作用。
• NOVEL BIS-AMIDE DERIVATIVE AND USE THEREOF
  申请人：University-Industry Cooperation Group of Kyung Hee University

  公开号：EP3050871B1

  公开（公告）日：2018-11-07
• Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections
  作者：Suhui Yang、Jyothi K.R.、Sangbin Lim、Tae Gyu Choi、Jin-Hwan Kim、Salima Akter、Miran Jang、Hyun-Jong Ahn、Hee-Young Kim、Marc P. Windisch、Daulat B. Khadka、Chao Zhao、Yifeng Jin、Insug Kang、Joohun Ha、Byung-Chul Oh、Meehyein Kim、Sung Soo Kim、Won-Jea Cho

  DOI：10.1021/acs.jmedchem.5b01064

  日期：2015.12.24

  Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct acting antivirals (DAAs), including inhibitors Of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening; the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed Selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics.