1,1-dimethylethyl [1(S)-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[1,2-dioxo-2-(2-propenylamino)ethyl]butyl]-amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate | 1020745-34-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: 1,1-dimethylethyl [1(S)-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[1,2-dioxo-2-(2-propenylamino)ethyl]butyl]-amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
• 英文别名: tert-butyl N-[(1S)-1-cyclohexyl-2-[(1S,2S,5R)-6,6-dichloro-2-[[1,2-dioxo-1-(prop-2-enylamino)hexan-3-yl]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
• CAS: 1020745-34-9
• 化学式: C₂₈H₄₂Cl₂N₄O₆
• 分子量: 601.571
• InChiKey: LFOSLZHNVNUFOO-LIELFMAKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  40
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  134
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  在 戴斯-马丁氧化剂 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 1,1-dimethylethyl [1(S)-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[1,2-dioxo-2-(2-propenylamino)ethyl]butyl]-amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
  参考文献：
  名称：

  Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue

  摘要：

  Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (K-i* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.002

文献信息

• Potent and selective small molecule NS3 serine protease inhibitors of Hepatitis C virus with dichlorocyclopropylproline as P2 residue
  作者：Kevin X. Chen、Bancha Vibulbhan、Weiying Yang、Kuo-Chi Cheng、Rong Liu、John Pichardo、Nancy Butkiewicz、F. George Njoroge

  DOI：10.1016/j.bmc.2007.11.002

  日期：2008.2.15

  Starting from a pentapeptide Hepatitis C virus NS3 protease inhibitor, a number of alpha-ketoamide inhibitors based on novel dichlorocyclopropylproline P2 core were synthesized and investigated for their HCV NS3 serine protease activity. The key intermediate 3,4-dichlorocyclopropylproline was obtained through a dichloro carbene insertion to 3,4-dehydroproline. The size of the molecules was reduced significantly through a series of truncations of the initial pentapeptide. By varying P1 side chain in length and size, potency and selectivity were improved. A variety of aliphatic carbamate and urea capping groups were examined. In general, compounds with urea cappings were more potent and selective than their carbamate counterparts. The most potent compound was a tert-butyl urea analog. Variations at P3 position were also investigated. Among the three residues incorporated, tert-leucine was clearly superior, leading to compounds that had excellent enzyme potency and selectivity. The most potent compound achieved cell-based replicon assay EC50 of 40 nM. The most promising compound of all had excellent potency in both enzyme (K-i* = 9 nM) and replicon assays (EC50 = 100 nM). Its bioavailabilities were above 10% in all three animal species (rats, monkeys, and dogs). It has provided a lead for future investigations. (c) 2007 Elsevier Ltd. All rights reserved.