ethyl (1R,2S)-2-ethenyl-1-[[(2S,4R)-1-(hex-5-enylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate | 862120-31-8

• 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: ethyl (1R,2S)-2-ethenyl-1-[[(2S,4R)-1-(hex-5-enylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate
• CAS: 862120-31-8
• 化学式: C₃₆H₄₂N₄O₆
• 分子量: 626.753
• InChiKey: KSMIACNIELXIEX-YHEQIKQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  46
• 可旋转键数：
  15
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl (1R,2S)-2-ethenyl-1-[[(2S,4R)-1-(hex-5-enylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate 在 dichloro(o-isporopoxyphenylmethylene)(triphenylphosphine)ruthenium(II) 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 20.0h， 生成 ethyl (1S,4R,6S,17R)-17-(7-methoxy-2-phenylquinolin-4-yl)oxy-2,14-dioxo-3,13,15-triazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylate
  参考文献：
  名称：

  Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

  摘要：

  A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K-i = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 mu M) inhibitor, displaying an excellent PK pro. le in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.10.004
• 作为产物：
  描述：

  1-氨基-5-己烯 、 ethyl (1R,2S)-1-((2S,4R)-1-(chlorocarbonyl)-4-((7-methoxy-2-phenylquinolin-4-yl)oxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropane-1-carboxylate 在 碳酸氢钠 作用下， 以 二氯甲烷 为溶剂， 生成 ethyl (1R,2S)-2-ethenyl-1-[[(2S,4R)-1-(hex-5-enylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yl)oxypyrrolidine-2-carbonyl]amino]cyclopropane-1-carboxylate
  参考文献：
  名称：

  Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors

  摘要：

  A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K-i = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 mu M) inhibitor, displaying an excellent PK pro. le in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2008.10.004

文献信息

• HCV NS-3 Serine Protease Inhibitors
  申请人：Rosenquist Asa

  公开号：US20100003216A1

  公开（公告）日：2010-01-07

  Compounds of the formula where the variables are as defined in the specification inhibit the NS3 protease of flavivirus sych as hepatitis C virus (HCV). The compounds comprise a novel linkage between a heterocyclic P2 unit and those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

  式中的变量如规范中所定义，可以抑制黄热病病毒(NS3蛋白酶)等黄病毒的蛋白酶，如丙型肝炎病毒(HCV)。这些化合物包括一个新的链接，连接一个杂环P2单位和那些离原生底物的名义剪切位点更远的抑制剂部位，该链接将离剪切位点远侧的肽键的方向与靠近剪切位点的肽键的方向相反。
• Hcv ns-3 serine protease inhibitors
  申请人：Rosenquist Asa

  公开号：US20070161574A1

  公开（公告）日：2007-07-12

  Compounds of the formula where the variables are as defined in the specification inhibit the NS3 protease of flavivirus such as hepatitis C virus (HCV). The compounds comprise a novel linkage between a heterocyclic P2 unit and those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

  式子中的变量如规范所定义，能够抑制类黄病毒的NS3蛋白酶，例如丙型肝炎病毒（HCV）。这些化合物包括一种新颖的连接方式，连接了一个杂环P2单元和抑制剂更远离天然底物裂解位点的部分，该连接方式反转了远离裂解位点的肽键方向相对于靠近裂解位点的肽键方向。
• US7608590B2
  申请人：——

  公开号：US7608590B2

  公开（公告）日：2009-10-27
• Discovery of novel, potent and bioavailable proline-urea based macrocyclic HCV NS3/4A protease inhibitors
  作者：Sandrine Vendeville、Magnus Nilsson、Herman de Kock、Tse-I Lin、Dmitry Antonov、Björn Classon、Susana Ayesa、Vladimir Ivanov、Per-Ola Johansson、Pia Kahnberg、Anders Eneroth、Kristina Wikstrom、Lotta Vrang、Michael Edlund、Stefan Lindström、Wim Van de Vreken、David McGowan、Abdellah Tahri、Lili Hu、Oliver Lenz、Frederic Delouvroy、Marleen Van Dooren、Natalie Kindermans、Dominique Surleraux、Piet Wigerinck、Åsa Rosenquist、Bertil Samuelsson、Kenneth Simmen、Pierre Raboisson

  DOI：10.1016/j.bmcl.2008.10.004

  日期：2008.12

  A novel series of P3-truncated macrocyclic HCV NS3/4A protease inhibitors containing a P2 proline-urea or carbamate scaffold was synthesized. Very potent inhibitors were obtained through the optimization of the macrocycle size, urea and proline substitution, and bioisosteric replacement of the P1 carboxylic acid moiety. Variation of the lipophilicity by introduction of small lipophilic substituents resulted in improved PK profiles, ultimately leading to compound 13Bh, an extremely potent (K-i = 0.1 nM, EC50 = 4.5 nM) and selective (CC50 (Huh-7 cells) > 50 mu M) inhibitor, displaying an excellent PK pro. le in rats characterized by an oral bioavailability of 54% and a high liver exposure after oral administration. (C) 2008 Elsevier Ltd. All rights reserved.