(1R,2S,5S)-methyl-6,6-dimethyl-3-((S)-2-(1-methylcyclohexyl)-2-((4-nitrophenoxy)carbonylamino)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate | 865469-43-8

• 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: (1R,2S,5S)-methyl-6,6-dimethyl-3-((S)-2-(1-methylcyclohexyl)-2-((4-nitrophenoxy)carbonylamino)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate
• 英文别名: methyl (1R,2S,5S)-6,6-dimethyl-3-[(2S)-2-(1-methylcyclohexyl)-2-[(4-nitrophenoxy)carbonylamino]acetyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate
• CAS: 865469-43-8
• 化学式: C₂₅H₃₃N₃O₇
• 分子量: 487.553
• InChiKey: JJNCHIXPJKVHRZ-LWYYNNOASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  131
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1R,2S,5S)-methyl-6,6-dimethyl-3-((S)-2-(1-methylcyclohexyl)-2-((4-nitrophenoxy)carbonylamino)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate 、 (S)-2-amino-3,3-dimethylbutyl ethylcarbamate hydrochloride 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 17.0h， 以0.46 g的产率得到
  参考文献：
  名称：

  Toward Second Generation Hepatitis C Virus NS3 Serine Protease Inhibitors: Discovery of Novel P4 Modified Analogues with Improved Potency and Pharmacokinetic Profile

  摘要：

  Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.

  DOI：

  10.1021/jm801616e
• 作为产物：
  描述：

  methyl (1R,2S,5S)-3-((S)-2-amino-2-(1-methylcyclohexyl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride 、 对硝基苯基氯甲酸酯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以3.74 g的产率得到(1R,2S,5S)-methyl-6,6-dimethyl-3-((S)-2-(1-methylcyclohexyl)-2-((4-nitrophenoxy)carbonylamino)acetyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate
  参考文献：
  名称：

  Toward Second Generation Hepatitis C Virus NS3 Serine Protease Inhibitors: Discovery of Novel P4 Modified Analogues with Improved Potency and Pharmacokinetic Profile

  摘要：

  Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.

  DOI：

  10.1021/jm801616e

文献信息

• [EN] SULFUR COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS NS3 SERINE PROTEASE<br/>[FR] COMPOSES SOUFRES EN TANT QU'INHIBITEURS DE LA PROTEASE SERINE NS3 DU VIRUS DE L'HEPATITE C
  申请人：SCHERING CORP

  公开号：WO2005087731A1

  公开（公告）日：2005-09-22

  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.

  本发明揭示了具有HCV蛋白酶抑制活性的新化合物，以及制备这些化合物的方法。在另一实施例中，本发明揭示了包含这些化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• Sulfur compounds as inhibitors of Hepatitis C virus NS3 serine protease
  申请人：Bennett Frank

  公开号：US20070042968A1

  公开（公告）日：2007-02-22

  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.

  本发明揭示了具有HCV蛋白酶抑制活性的新化合物，以及制备这些化合物的方法。在另一种实施方式中，本发明揭示了包含这些化合物的药物组合物，以及使用它们治疗与HCV蛋白酶相关的疾病的方法。
• US8067379B2
  申请人：——

  公开号：US8067379B2

  公开（公告）日：2011-11-29
• Toward Second Generation Hepatitis C Virus NS3 Serine Protease Inhibitors: Discovery of Novel P4 Modified Analogues with Improved Potency and Pharmacokinetic Profile
  作者：Ashok Arasappan、Angela I. Padilla、Edwin Jao、Frank Bennett、Stephane L. Bogen、Kevin X. Chen、Russell E. Pike、Mousumi Sannigrahi、Joana Soares、Srikanth Venkatraman、Bancha Vibulbhan、Anil K. Saksena、Viyyoor Girijavallabhan、Xiao Tong、Kuo-Chi Cheng、F. George Njoroge

  DOI：10.1021/jm801616e

  日期：2009.5.14

  Hepatitis C virus (HCV) infection is a global health crisis leading to liver cirrhosis, hepatocellular carcinoma, and liver failure in humans. Recently, we disclosed the discovery of Boceprevir, SCH 503034 (1), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that is currently undergoing phase III clinical trials. Our efforts toward a second generation HCV NS3 serine protease inhibitor were directed at improving the overall profile of the inhibitor. This article will elaborate on our studies leading to the discovery of new P4 modified inhibitors with enhanced potency and improved oral bioavailability. Thus, introduction of ether and carbamate-derived P4 moieties resulted in improving the replicon potency significantly. Incorporation of the P' secondary amide residue afforded significant improvement in pharmacokinetic properties. Combining the preferred moieties, identified from comprehensive SAR studies, resulted in inhibitors that displayed superior potency and very good oral as well as target organ exposure in rats.