(16aS,17aR,17bS)-13(S)-[[[[1(S)-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-2,2-dimethylpropyl]amino]carbonyl]amino]octadecahydro-17,17-dimethyl-α,1,14-trioxo-N-(2-propenyl)-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecine-3(S)-acetamide | 1100795-76-3

• 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: (16aS,17aR,17bS)-13(S)-[[[[1(S)-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-2,2-dimethylpropyl]amino]carbonyl]amino]octadecahydro-17,17-dimethyl-α,1,14-trioxo-N-(2-propenyl)-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecine-3(S)-acetamide
• 英文别名: 2-[(3S,13S,16S,17R,19S)-3-({[(2S)-1-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-3,3-dimethylbutan-2-yl]carbamoyl}amino)-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.0^{17,19}]icosan-13-yl]-2-oxo-N-(prop-2-en-1-yl)acetamide；2-[(3S,13S,16S,17R,19S)-3-[[(2S)-1-(1,3-dioxoisoindol-2-yl)-3,3-dimethylbutan-2-yl]carbamoylamino]-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.017,19]icosan-13-yl]-2-oxo-N-prop-2-enylacetamide
• CAS: 1100795-76-3
• 化学式: C₄₀H₅₆N₆O₇
• 分子量: 732.921
• InChiKey: IJIYLULZQBQFEU-MACKVBDYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  53
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  174
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-[(2S)-2-isocyanato-3,3-dimethylbutyl]isoindole-1,3-dione 、 2-[(3S,13S,16S,17R,19S)-3-amino-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.017,19]icosan-13-yl]-2-oxo-N-prop-2-enylacetamide 在 N-甲基吗啉 作用下， 以 二氯甲烷 为溶剂， 生成 (16aS,17aR,17bS)-13(S)-[[[[1(S)-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-2,2-dimethylpropyl]amino]carbonyl]amino]octadecahydro-17,17-dimethyl-α,1,14-trioxo-N-(2-propenyl)-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecine-3(S)-acetamide
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of P₁−P₃ Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease

  摘要：

  Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P-1-P-3 macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P-3 imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.

  DOI：

  10.1021/jm800940u

文献信息

• Macrocyclic Inhibitors of Hepatitis C Virus NS3 Serine Protease
  申请人：Venkatraman Srikanth

  公开号：US20110150835A1

  公开（公告）日：2011-06-23

  The present invention discloses novel compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such compounds as well as methods of using them to treat disorders associated with the HCV protease.
• US7592419B2
  申请人：——

  公开号：US7592419B2

  公开（公告）日：2009-09-22
• Discovery and Structure−Activity Relationship of P₁−P₃ Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease
  作者：Srikanth Venkatraman、Francisco Velazquez、Wanli Wu、Melissa Blackman、Kevin X. Chen、Stephane Bogen、Latha Nair、Xiao Tong、Robert Chase、Andrea Hart、Sony Agrawal、John Pichardo、Andrew Prongay、Kuo-Chi Cheng、Viyyoor Girijavallabhan、John Piwinski、Neng-Yang Shih、F. George Njoroge

  DOI：10.1021/jm800940u

  日期：2009.1.22

  Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P-1-P-3 macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P-3 imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.