(3R,5S)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-5-[[(1R,2S)-2-ethenyl-1-methoxycarbonylcyclopropyl]carbamoyl]pyrrolidine-3-carboxylic acid | 1308396-66-8

• 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: (3R,5S)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-5-[[(1R,2S)-2-ethenyl-1-methoxycarbonylcyclopropyl]carbamoyl]pyrrolidine-3-carboxylic acid
• CAS: 1308396-66-8
• 化学式: C₂₅H₃₇N₃O₈
• 分子量: 507.584
• InChiKey: VVYAYTLQRNLYKM-RQCXFBAXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  151
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (3R,5S)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-5-[[(1R,2S)-2-ethenyl-1-methoxycarbonylcyclopropyl]carbamoyl]pyrrolidine-3-carboxylic acid 在 氢溴酸 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 、 水 为溶剂， 反应 3.0h， 生成 methyl (1R,2S)-1-[[(2S,4R)-4-(2-bromoacetyl)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate
  参考文献：
  名称：

  Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus NS3 serine protease

  摘要：

  Inhibitors of hepatitis C virus NS3 serine protease often incorporate a large P2 moiety to interact with the surface of the enzyme while shielding part of the catalytic triad. This feature is important in many inhibitors in order to have the necessary potency needed for efficacy. In this Letter we explore some new P2 motifs to further exploit this region of the enzyme. In a continuing effort to replace the often found 4-hydroxyproline P2 core found in the majority of inhibitors for this target, various directly attached aryl derivatives were evaluated. Of these, the 2,4-disubstituted thiazole core proved to be the most interesting. SAR around this motif has lead to compounds with K-i's in the high picomolar range and provided cellular potencies in the single digit nM range. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.046
• 作为产物：
  描述：

  methyl (1R,2S)-1-[[(2S,4R)-4-cyano-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-2-ethenylcyclopropane-1-carboxylate 在 盐酸 、 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 17.5h， 生成 (3R,5S)-1-[(2S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl]-5-[[(1R,2S)-2-ethenyl-1-methoxycarbonylcyclopropyl]carbamoyl]pyrrolidine-3-carboxylic acid
  参考文献：
  名称：

  Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus NS3 serine protease

  摘要：

  Inhibitors of hepatitis C virus NS3 serine protease often incorporate a large P2 moiety to interact with the surface of the enzyme while shielding part of the catalytic triad. This feature is important in many inhibitors in order to have the necessary potency needed for efficacy. In this Letter we explore some new P2 motifs to further exploit this region of the enzyme. In a continuing effort to replace the often found 4-hydroxyproline P2 core found in the majority of inhibitors for this target, various directly attached aryl derivatives were evaluated. Of these, the 2,4-disubstituted thiazole core proved to be the most interesting. SAR around this motif has lead to compounds with K-i's in the high picomolar range and provided cellular potencies in the single digit nM range. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.046

文献信息

• Discovery of novel P2 substituted 4-biaryl proline inhibitors of hepatitis C virus NS3 serine protease
  作者：Murray D. Bailey、Teddy Halmos、Christopher T. Lemke

  DOI：10.1016/j.bmcl.2013.05.046

  日期：2013.8

  Inhibitors of hepatitis C virus NS3 serine protease often incorporate a large P2 moiety to interact with the surface of the enzyme while shielding part of the catalytic triad. This feature is important in many inhibitors in order to have the necessary potency needed for efficacy. In this Letter we explore some new P2 motifs to further exploit this region of the enzyme. In a continuing effort to replace the often found 4-hydroxyproline P2 core found in the majority of inhibitors for this target, various directly attached aryl derivatives were evaluated. Of these, the 2,4-disubstituted thiazole core proved to be the most interesting. SAR around this motif has lead to compounds with K-i's in the high picomolar range and provided cellular potencies in the single digit nM range. (C) 2013 Elsevier Ltd. All rights reserved.