N-cyclohexyl-2-[(3,4-dimethoxyphenyl)-(2-1H-indol-3-ylacetyl)-amino]-2-(2,3,4-trimethoxyphenyl)acetamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-cyclohexyl-2-[(3,4-dimethoxyphenyl)-(2-1H-indol-3-ylacetyl)-amino]-2-(2,3,4-trimethoxyphenyl)acetamide
• 英文别名: N-cyclohexyl-2-[(3,4-dimethoxyphenyl)-(2-1H-indol-3-ylacetyl)amino]-2-(2,3,4-trimethoxyphenyl)acetamide；N-cyclohexyl-2-(N-[2-(1H-indol-3-yl)acetyl]-3,4-dimethoxyanilino)-2-(2,3,4-trimethoxyphenyl)acetamide
• 化学式: C₃₅H₄₁N₃O₇
• 分子量: 615.726
• InChiKey: PGARCXVFMOSUEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  45
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  3-吲哚乙酸 、 异氰环已烷 、 3,4-二甲氧基苯胺 、 2,3,4-三甲氧基苯甲醛 以 2,2,2-三氟乙醇 为溶剂， 以80%的产率得到N-cyclohexyl-2-[(3,4-dimethoxyphenyl)-(2-1H-indol-3-ylacetyl)-amino]-2-(2,3,4-trimethoxyphenyl)acetamide
  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

• NOVEL BIS-AMIDE DERIVATIVE AND USE THEREOF
  申请人：UNIVERSITY-INDUSTRY COOPERATION GROUP OF KYUNG HEE UNIVERSITY

  公开号：US20160297751A1

  公开（公告）日：2016-10-13

  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 (K off ). 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.
• 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.