1,1-dimethylethyl [(13S,16aS,17aR,17bS)-3-(2-amino-1,2-dioxoethyl)octadecohydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13-yl]carbamate | 1100795-55-8

• 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: 1,1-dimethylethyl [(13S,16aS,17aR,17bS)-3-(2-amino-1,2-dioxoethyl)octadecohydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13-yl]carbamate
• 英文别名: tert-butyl N-[(3S,13S,16S,17R,19S)-13-(carbamoylcarbonyl)-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.0^{17,19}]icosan-3-yl]carbamate；tert-butyl N-[(3S,13S,16S,17R,19S)-18,18-dimethyl-13-oxamoyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.017,19]icosan-3-yl]carbamate
• CAS: 1100795-55-8
• 化学式: C₂₇H₄₄N₄O₆
• 分子量: 520.67
• InChiKey: APKSIFMITNSEJK-HVTWWXFQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  148
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl [(13S,16aS,17aR,17bS)-3-(2-amino-1,2-dioxoethyl)octadecohydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13-yl]carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 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-oxoacetamide
  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
• 作为产物：
  描述：

  tert-butyl N-[(3S,13S,16S,17R,19S)-13-(2-amino-1-hydroxy-2-oxoethyl)-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.017,19]icosan-3-yl]carbamate 在 二氯乙酸 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲苯 为溶剂， 生成 1,1-dimethylethyl [(13S,16aS,17aR,17bS)-3-(2-amino-1,2-dioxoethyl)octadecohydro-17,17-dimethyl-1,14-dioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecin-13-yl]carbamate
  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

• 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.