(1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide | 1095263-17-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide
• 英文别名: (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexane-1-carboxamide
• CAS: 1095263-17-4
• 化学式: C₂₃H₂₅FN₄O₂
• 分子量: 408.476
• InChiKey: DFWBUMFMCGXLEW-HZPDHXFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  89
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid 在 乙酸酐 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 (1R,2R)-N-(1-cyanocyclopropyl)-2-[(6-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide
  参考文献：
  名称：

  (1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis

  摘要：

  Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.

  DOI：

  10.1021/jm3007257

文献信息

• Novel Compound - 827
  申请人：Dossetter Alexander Graham

  公开号：US20090012077A1

  公开（公告）日：2009-01-08

  The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K.

  本发明涉及用于治疗与半胱氨酸蛋白酶活性相关疾病的化合物和组合物。这些化合物是半胱氨酸蛋白酶的可逆抑制剂，包括卡特普辛B、K、C、F、H、L、O、S、W和X。特别感兴趣的是与卡特普辛K相关的疾病。
• 1-CYANOCYCLOPROPYL-DERIVATIVES AS CATHEPSIN K INHIBITORS
  申请人：AstraZeneca AB

  公开号：EP2170879B1

  公开（公告）日：2013-01-16
• US8008279B2
  申请人：——

  公开号：US8008279B2

  公开（公告）日：2011-08-30
• (1<i>R</i>,2<i>R</i>)-<i>N</i>-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-<i>b</i>]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inhibitor for the Treatment of Osteoarthritis
  作者：Alexander G. Dossetter、Howard Beeley、Jonathan Bowyer、Calum R. Cook、James J. Crawford、Jonathan E. Finlayson、Nicola M. Heron、Christine Heyes、Adrian J. Highton、Julian A. Hudson、Anja Jestel、Peter W. Kenny、Stephan Krapp、Scott Martin、Philip A. MacFaul、Thomas M. McGuire、Pablo Morentin Gutierrez、Andrew D. Morley、Jeffrey J. Morris、Ken M. Page、Lyn Rosenbrier Ribeiro、Helen Sawney、Stefan Steinbacher、Caroline Smith、Madeleine Vickers

  DOI：10.1021/jm3007257

  日期：2012.7.26

  Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.