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(1R,2S,5S)-3-[(2S)-2-[[(2S)-1-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)-3,3-dimethylbutan-2-yl]carbamoylamino]-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | 1063968-44-4

中文名称
——
中文别名
——
英文名称
(1R,2S,5S)-3-[(2S)-2-[[(2S)-1-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)-3,3-dimethylbutan-2-yl]carbamoylamino]-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
英文别名
——
(1R,2S,5S)-3-[(2S)-2-[[(2S)-1-(4,4-dimethyl-2,6-dioxopiperidin-1-yl)-3,3-dimethylbutan-2-yl]carbamoylamino]-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid化学式
CAS
1063968-44-4
化学式
C28H46N4O6
mdl
——
分子量
534.696
InChiKey
YMUMRDBQUURREI-CEDHKZHLSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

计算性质

  • 辛醇/水分配系数(LogP):
    3.4
  • 重原子数:
    38
  • 可旋转键数:
    8
  • 环数:
    3.0
  • sp3杂化的碳原子比例:
    0.82
  • 拓扑面积:
    136
  • 氢给体数:
    3
  • 氢受体数:
    6

反应信息

  • 作为反应物:
    参考文献:
    名称:
    Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease
    摘要:
    The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
    DOI:
    10.1021/jm801238q
  • 作为产物:
    参考文献:
    名称:
    Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease
    摘要:
    The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.
    DOI:
    10.1021/jm801238q
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文献信息

  • Potent ketoamide inhibitors of HCV NS3 protease derived from quaternized P1 groups
    作者:Srikanth Venkatraman、Francisco Velazquez、Wanli Wu、Melissa Blackman、Vincent Madison、F. George Njoroge
    DOI:10.1016/j.bmcl.2010.02.051
    日期:2010.4
    Blood borne hepatitis C infections are the primary cause for liver cirrhosis and hepatocellular carcinoma. HCV NS3 protease, a pivotal enzyme in the replication cycle of HCV virus has been the primary target for development of new drug candidates. Boceprevir and telaprevir are two novel ketoamide derived inhibitors that are currently undergoing phase-III clinical trials. These inhibitors include ketoamide functionality as serine trap and have an acidic alpha-ketoamide center that undergoes epimerization under physiological conditions. Our initial attempts to arrest this epimerization by introducing quaternary amino acids at P-1 had resulted in significantly diminished activity. In this manuscript we describe alpha quaternized P-1 group that result in potent inhibitors in the enzyme assay and demonstrate cellular activity comparable to boceprevir. (C) 2010 Elsevier Ltd. All rights reserved.
  • Potent aza-peptide derived inhibitors of HCV NS3 protease
    作者:Srikanth Venkatraman、Wanli Wu、Neng-Yang Shih、F. George Njoroge
    DOI:10.1016/j.bmcl.2009.06.060
    日期:2009.8
    Chronic hepatitis C infection is the primary cause for cirrhosis of the liver and hepatocellular carcinoma leading to liver failure and transplantation. The etiological agent hepatitis C virus produces a single positive strand RNA that is processed further with the help of NS3 serine protease to produce mature virus. Inhibition of this protease can potentially be used to develop drugs for HCV infections. Boceprevir is a ketoamide derived novel inhibitor of HCV NS3 protease that has been progressed to clinical trials and proven to be efficacious in humans. Herein, we report our efforts in identifying an aza-peptide derivative as a potential second generation compound, that lacks electrophilic ketoamide group and are potent in enzyme and replicon assay. (C) 2009 Published by Elsevier Ltd.
  • HYDRAZIDO-PEPTIDES AS INHIBITORS OF HCV NS3-PROTEASE
    申请人:Venkatraman Srikanth
    公开号:US20100104534A1
    公开(公告)日:2010-04-29
    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.
  • [EN] HYDRAZIDO-PEPTIDES AS INHIBITORS OF HCV NS3-PROTEASE<br/>[FR] PEPTIDES HYDRAZIDO EN TANT QU'INHIBITEURS DE LA PROTÉASE NS3 DU HCV
    申请人:SCHERING CORP
    公开号:WO2008118332A2
    公开(公告)日:2008-10-02
    [EN] 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.
    [FR] La présente invention concerne de nouveaux composés ayant une activité inhibitrice de la protéase du HCV ainsi que des procédés pour les préparer. Dans un autre mode de réalisation, l'invention décrit des compositions pharmaceutiques comprenant ces composés ainsi que leurs procédés d'utilisation pour traiter les troubles associés à la protéase du HCV.
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