(1R,2S)-1-{[(1R,2R,4R)-2-hex-5-enylcarbamoyl-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-cyclopentanecarbonyl]amino}-2-vinylcyclopropanecarboxylic acid ethyl ester | 862174-87-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (1R,2S)-1-{[(1R,2R,4R)-2-hex-5-enylcarbamoyl-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-cyclopentanecarbonyl]amino}-2-vinylcyclopropanecarboxylic acid ethyl ester
• CAS: 862174-87-6
• 化学式: C₃₇H₄₃N₃O₆
• 分子量: 625.765
• InChiKey: OCSFTLCCZNXAGC-HIWXKBTGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.78
• 重原子数：
  46.0
• 可旋转键数：
  15.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  115.85
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (1R,2S)-1-{[(1R,2R,4R)-2-hex-5-enylcarbamoyl-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-cyclopentanecarbonyl]amino}-2-vinylcyclopropanecarboxylic acid ethyl ester 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 生成 (1R,4R,6S,15R,17S)-17-(7-methoxy-2-phenylquinolin-4-yl)oxy-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid
  参考文献：
  名称：

  计算机评价大环抑制剂与 HCV NS3 蛋白酶之间的分子相互作用。抗病毒药效团位点的对接与鉴定

  摘要：

  摘要 一系列计算方法 DFT/QSAR/POM 方法已用于更好地了解有关 13 种抑制剂衍生物的药物特性，这些衍生物包含 P2 环戊烷 P1 羧酸部分 (1-9) 或 P1 环丙基酰基磺酰胺( 10-13 )。为了进一步认识结合相互作用及其活性趋势，利用HCV进行了分子对接研究，可用于准确预测配体与受体的相互作用。QSAR 模型是通过使用多元线性回归 (MLR) 和主成分分析 (PCA) 方法开发的。统计结果表明多重相关系数R 2 = 0.840，这显示了良好的估计稳定性，并显示了所研究化合物的 HCV NS3 蛋白酶与其电子接受能力之间的显着相关性。化合物1-13的物理化学性质的 POM 分析表明它们带有 (O1, O2) 和/或 (O1, O2, O3) 抗病毒口袋，其中所有氧原子都是 Osp2 并带有负电荷。与参考配体 (F9K) 类似，最活跃的化合物10深入结合到 NS3 蛋白酶的结合腔中，与残基

  DOI：

  10.1080/07391102.2022.2029571
• 作为产物：
  描述：

  (1R,2R,4S)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-cyclopenteanecarboxylic acid tert-butyl ester 、 1-氨基-5-己烯 在 三乙基硅烷 、 三氟乙酸 、 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 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以70%的产率得到(1R,2S)-1-{[(1R,2R,4R)-2-hex-5-enylcarbamoyl-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-cyclopentanecarbonyl]amino}-2-vinylcyclopropanecarboxylic acid ethyl ester
  参考文献：
  名称：

  Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: Use of cyclopentane and cyclopentene P2-motifs

  摘要：

  Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding PI acylsulfonamides had superior potencies over the corresponding PI carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K-i value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype lb. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assav and lacking the P4 substituent, a finding which Should facilitate the development of orally active small molecule inhibitors against the HCV protease. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.07.027