(2S,2'S)-tert-butyl 2,2'-N,N'-(4,4'-((E)-ethene-1,2-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (2S,2'S)-tert-butyl 2,2'-N,N'-(4,4'-((E)-ethene-1,2-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
• 英文别名: tert-butyl (2S)-2-[[4-[(E)-2-[4-[[(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carbonyl]amino]phenyl]ethenyl]phenyl]carbamoyl]pyrrolidine-1-carboxylate
• 化学式: C₃₄H₄₄N₄O₆
• 分子量: 604.747
• InChiKey: ASPXUNVCSVWBBN-WOUJKONLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  44
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,2'S)-tert-butyl 2,2'-N,N'-(4,4'-((E)-ethene-1,2-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 (2S,2'S)-N,N'-(4,4'-((E)-ethene-1,2-diyl)bis(4,1-phenylene))bis(1-(quinazoline-4-carbonyl)pyrrolidine-2-carboxamide)
  参考文献：
  名称：

  HCV NS5A Replication Complex Inhibitors. Part 4.1 Optimization for Genotype 1a Replicon Inhibitory Activity

  摘要：

  A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.

  DOI：

  10.1021/jm301796k
• 作为产物：
  描述：

  4,4'-Diaminostilbene dihydrochloride 在 ammonium hydroxide 、 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 18.25h， 生成 (2S,2'S)-tert-butyl 2,2'-N,N'-(4,4'-((E)-ethene-1,2-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate
  参考文献：
  名称：

  HCV NS5A Replication Complex Inhibitors. Part 4.1 Optimization for Genotype 1a Replicon Inhibitory Activity

  摘要：

  A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor.

  DOI：

  10.1021/jm301796k

文献信息

• Inhibitors of HCV replication
  申请人：Serrano-Wu Michael

  公开号：US20060276511A1

  公开（公告）日：2006-12-07

  Compounds having the structure of formula I are described. The compounds can inhibit hepatitis C virus (HCV) replication, and in particular can inhibit the function of the HCV NS5A protein.

  具有公式I结构的化合物被描述。这些化合物可以抑制丙型肝炎病毒（HCV）的复制，特别是可以抑制HCV NS5A蛋白的功能。
• HCV NS5A replication complex inhibitors. Part 3: discovery of potent analogs with distinct core topologies
  作者：Omar D. Lopez、Van N. Nguyen、Denis R. St. Laurent、Makonen Belema、Michael H. Serrano-Wu、Jason T. Goodrich、Fukang Yang、Yuping Qiu、Amy S. Ripka、Peter T. Nower、Lourdes Valera、Mengping Liu、Donald R. O’Boyle、Jin-Hua Sun、Robert A. Fridell、Julie A. Lemm、Min Gao、Andrew C. Good、Nicholas A. Meanwell、Lawrence B. Snyder

  DOI：10.1016/j.bmcl.2012.11.086

  日期：2013.2

  In a recent disclosure,(1) we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting < 10 nM EC50 in a genotype 1b replicon assay. (c) 2012 Elsevier Ltd. All rights reserved.
• HCV NS5A replication complex inhibitors. Part 2: Investigation of stilbene prolinamides
  作者：Denis R. St. Laurent、Makonen Belema、Min Gao、Jason Goodrich、Ramesh Kakarla、Jay O. Knipe、Julie A. Lemm、Mengping Liu、Omar D. Lopez、Van N. Nguyen、Peter T. Nower、Donald O’Boyle、Yuping Qiu、Jeffrey L. Romine、Michael H. Serrano-Wu、Jin-Hua Sun、Lourdes Valera、Fukang Yang、Xuejie Yang、Nicholas A. Meanwell、Lawrence B. Snyder

  DOI：10.1016/j.bmcl.2012.08.049

  日期：2012.10

  In a previous disclosure,(1) we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection. (C) 2012 Elsevier Ltd. All rights reserved.
• INHIBITORS OF HCV REPLICATION
  申请人：Bristol-Myers Squibb Company

  公开号：EP1893573B1

  公开（公告）日：2010-07-21
• US8143288B2
  申请人：——

  公开号：US8143288B2

  公开（公告）日：2012-03-27