(16aS,17aR,17bS)-13(S)-[[[[1(S)-cyclohexyl-2-cyclopropyl-2-oxoethyl]amino]carbonyl]amino]octadecohydro-17,17-dimethyl-α,1,14-trioxo-2H-cyclopropa[3,4]pyrrolo[1,2-a][1,4]diazacyclohexadecine-3(S)-acetamide | 1100795-58-1

• 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)-cyclohexyl-2-cyclopropyl-2-oxoethyl]amino]carbonyl]amino]octadecohydro-17,17-dimethyl-α,1,14-trioxo-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-({[(1S)-1-cyclohexyl-2-cyclopropyl-2-oxoethyl]carbamoyl}amino)-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.0^{17,19}]icosan-13-yl]-2-oxoacetamide；2-[(3S,13S,16S,17R,19S)-3-[[(1S)-1-cyclohexyl-2-cyclopropyl-2-oxoethyl]carbamoylamino]-18,18-dimethyl-2,15-dioxo-1,14-diazatricyclo[14.4.0.017,19]icosan-13-yl]-2-oxoacetamide
• CAS: 1100795-58-1
• 化学式: C₃₄H₅₃N₅O₆
• 分子量: 627.825
• InChiKey: WRVODXMWQBCAPK-QCOJBMJGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  45
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  168
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (2S)-2-cyclohexyl-1-cyclopropyl-2-isocyanatoethanone 、 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 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)-cyclohexyl-2-cyclopropyl-2-oxoethyl]amino]carbonyl]amino]octadecohydro-17,17-dimethyl-α,1,14-trioxo-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

• US7592419B2
  申请人：——

  公开号：US7592419B2

  公开（公告）日：2009-09-22
• [EN] METHOD OF INHIBITING CATHEPSIN ACTIVITY<br/>[FR] PROCEDE D'INHIBITION DE L'ACTIVITE DE CATHEPSINE
  申请人：SCHERING CORP

  公开号：WO2006113942A2

  公开（公告）日：2006-10-26

  [EN] The present invention provides methods of inhibiting cathepsin activity in a subject in need thereof comprising administering to said subject an effective amount of at least one compound of various formulae (e.g., formula I-XXVI) disclosed herein. The present invention also provides methods of treatment of various diseases utilizing the foregoing compounds.
  [FR] L'invention concerne des procédés d'inhibition de l'activité de la cathepsine chez un sujet le nécessitant qui consiste à administrer à ce sujet une quantité efficace d'au moins un composé de diverses formules (par exemple, formule I-XXVI). Cette invention concerne également des procédés de traitement de diverses maladies au moyen des composés susmentionnés.
• 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.