(S)-tert-butyl (1-(4-((6-methoxy-2-phenylpyrimidin-4-yl)oxy)phenyl)-2-oxo-2-((2-((pent-4-en-1-ylsulfonyl)carbamoyl)phenyl)amino)ethyl)carbamate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-tert-butyl (1-(4-((6-methoxy-2-phenylpyrimidin-4-yl)oxy)phenyl)-2-oxo-2-((2-((pent-4-en-1-ylsulfonyl)carbamoyl)phenyl)amino)ethyl)carbamate
• 英文别名: tert-butyl N-[(1S)-1-[4-(6-methoxy-2-phenylpyrimidin-4-yl)oxyphenyl]-2-oxo-2-[2-(pent-4-enylsulfonylcarbamoyl)anilino]ethyl]carbamate
• 化学式: C₃₆H₃₉N₅O₈S
• 分子量: 701.8
• InChiKey: BJHYKAIRMZXQJV-HKBQPEDESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  50
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  183
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl (1-(4-((6-methoxy-2-phenylpyrimidin-4-yl)oxy)phenyl)-2-oxo-2-((2-((pent-4-en-1-ylsulfonyl)carbamoyl)phenyl)amino)ethyl)carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成
  参考文献：
  名称：

  Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles

  摘要：

  With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.10.010
• 作为产物：
  描述：

  解草啶 在 甲醇 、 potassium tert-butylate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 10.67h， 生成 (S)-tert-butyl (1-(4-((6-methoxy-2-phenylpyrimidin-4-yl)oxy)phenyl)-2-oxo-2-((2-((pent-4-en-1-ylsulfonyl)carbamoyl)phenyl)amino)ethyl)carbamate
  参考文献：
  名称：

  Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles

  摘要：

  With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.10.010

文献信息

• Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
  作者：Anna Lampa、Hiba Alogheli、Angelica E. Ehrenberg、Eva Åkerblom、Richard Svensson、Per Artursson、U. Helena Danielson、Anders Karlén、Anja Sandström

  DOI：10.1016/j.bmc.2014.10.010

  日期：2014.12

  With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties. (C) 2014 Elsevier Ltd. All rights reserved.