(1R,2R)-2-{[4-(3,4-dimethoxyphenyl)piperazin-1-yl]carbonyl}cyclohexanecarboxylic acid (1-cyanocyclopropyl)amide | 1095535-37-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (1R,2R)-2-{[4-(3,4-dimethoxyphenyl)piperazin-1-yl]carbonyl}cyclohexanecarboxylic acid (1-cyanocyclopropyl)amide
• 英文别名: (1R,2R)-N-(1-cyanocyclopropyl)-2-[4-(3,4-dimethoxyphenyl)piperazine-1-carbonyl]cyclohexane-1-carboxamide
• CAS: 1095535-37-7
• 化学式: C₂₄H₃₂N₄O₄
• 分子量: 440.542
• InChiKey: JZBYJYKJCCEKMS-RTBURBONSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  94.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  反式-1,2-环己二羧酸酐 、 1-氨基-1-环丙基腈盐酸盐 、 1-(3,4-二甲氧基苯基)哌嗪 在 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 N,N-二甲基甲酰胺 为溶剂， 反应 90.0h， 以58%的产率得到(1R,2R)-2-{[4-(3,4-dimethoxyphenyl)piperazin-1-yl]carbonyl}cyclohexanecarboxylic acid (1-cyanocyclopropyl)amide
  参考文献：
  名称：

  Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl Ring and Design of Isosteres Yielding Orally Available Cathepsin K Inhibitors

  摘要：

  Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH3O)(2)Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif: Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).

  DOI：

  10.1021/jm301119s

文献信息

• [EN] CYANOCYCLOPROPYLCARBOXAMIDES AS CATHEPSIN INHIBITORS<br/>[FR] CYANOCYCLOPROPYLCARBOXAMIDES EN TANT QU'INHIBITEURS DE CATHEPSINE
  申请人：ASTRAZENECA AB

  公开号：WO2009001127A1

  公开（公告）日：2008-12-31

  [EN] The present invention relates to compounds of formula (I) 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.
  [FR] L'invention concerne des composés de formule (I) destinés au traitement de maladies associées à l'activité de la cystéine protéase. Les composés selon l'invention sont des inhibiteurs réversibles de cystéines protéases, notamment des cathepsines B, K, C, F, H, L, O, S, W et X. Les maladies associées à la cathepsine K font l'objet d'un intérêt particulier.
• Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl Ring and Design of Isosteres Yielding Orally Available Cathepsin K Inhibitors
  作者：James J. Crawford、Peter W. Kenny、Jonathan Bowyer、Calum R. Cook、Jonathan E. Finlayson、Christine Heyes、Adrian J. Highton、Julian A. Hudson、Anja Jestel、Stephan Krapp、Scott Martin、Philip A. MacFaul、Benjamin P. McDermott、Thomas M. McGuire、Andrew D. Morley、Jeffrey J. Morris、Ken M. Page、Lyn Rosenbrier Ribeiro、Helen Sawney、Stefan Steinbacher、Caroline Smith、Alexander G. Dossetter

  DOI：10.1021/jm301119s

  日期：2012.10.25

  Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH3O)(2)Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif: Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).