N-{4-[4-(3-aminophenyl)piperazin-1-yl]butyl}-C-cyclohexylmethanesulfonamide | 740873-05-6

• 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: N-{4-[4-(3-aminophenyl)piperazin-1-yl]butyl}-C-cyclohexylmethanesulfonamide
• 英文别名: N-{4-[4-(3-aminophenyl)piperazin-1-yl]butyl}-1-cyclohexylmethanesulfonamide；N-[4-[4-(3-aminophenyl)piperazin-1-yl]butyl]-1-cyclohexylmethanesulfonamide
• CAS: 740873-05-6
• 化学式: C₂₁H₃₆N₄O₂S
• 分子量: 408.608
• InChiKey: BEOPHYTYWWHDFZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  N-{4-[4-(3-aminophenyl)piperazin-1-yl]butyl}-C-cyclohexylmethanesulfonamide 、 乙酰氯 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以89%的产率得到N-[3-[4-[4-[(环己基甲基磺酰基)氨基]丁基]哌嗪-1-基]苯基]乙酰胺
  参考文献：
  名称：

  An Integrated in Silico 3D Model-Driven Discovery of a Novel, Potent, and Selective Amidosulfonamide 5-HT_1A Agonist (PRX-00023) for the Treatment of Anxiety and Depression

  摘要：

  We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl] phenyl} acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha(1)-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.

  DOI：

  10.1021/jm0508641
• 作为产物：
  描述：

  间硝基苯胺 在 盐酸 、 potassium carbonate 、 三乙胺 、 tin(ll) chloride 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯苯 为溶剂， 反应 98.5h， 生成 N-{4-[4-(3-aminophenyl)piperazin-1-yl]butyl}-C-cyclohexylmethanesulfonamide
  参考文献：
  名称：

  An Integrated in Silico 3D Model-Driven Discovery of a Novel, Potent, and Selective Amidosulfonamide 5-HT_1A Agonist (PRX-00023) for the Treatment of Anxiety and Depression

  摘要：

  We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl] phenyl} acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha(1)-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.

  DOI：

  10.1021/jm0508641

文献信息

• Arylpiperazinyl compounds
  申请人：——

  公开号：US20040220192A1

  公开（公告）日：2004-11-04

  The invention relates to 5-HT receptor agonists or antagonists. Novel arylpiperazinyl sulfonamide compounds represented by Formula I, and synthesis and uses thereof for treating diseases including those mediated directly or indirectly by 5-HT receptors, are disclosed. Such conditions include central nervous system disorders such as generalized anxiety disorder, ADD/ADHD, neural injury, stroke, and migraine. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also included.

  该发明涉及5-HT受体激动剂或拮抗剂。公开了由公式I表示的新型芳基哌嗪磺酰胺化合物及其合成和用于治疗直接或间接由5-HT受体介导的疾病的用途。这些疾病包括中枢神经系统疾病，如广泛性焦虑症、ADD/ADHD、神经损伤、中风和偏头痛。还包括制备方法、新型中间体和其制药盐。
• Arylpiperazinyl Compounds
  申请人：Dhanoa S. Dale

  公开号：US20080027066A1

  公开（公告）日：2008-01-31

  The invention relates to 5-HT receptor agonists or antagonists. Novel arylpiperazinyl sulfonamide compounds represented by Formula I, and synthesis and uses thereof for treating diseases including those mediated directly or indirectly by 5-HT receptors, are disclosed. Such conditions include central nervous system disorders such as generalized anxiety disorder, ADD/ADHD, neural injury, stroke, and migraine. Methods of preparation and novel intermediates and pharmaceutical salts thereof are also included.

  该发明涉及5-HT受体激动剂或拮抗剂。公开了由式I表示的新型芳基哌嗪磺酰胺化合物及其合成和用途，用于治疗包括直接或间接通过5-HT受体介导的疾病。这些疾病包括中枢神经系统疾病，如广泛性焦虑症，ADD / ADHD，神经损伤，中风和偏头痛。还包括制备方法、新型中间体和药物盐。
• [EN] NEW ARYLPIPERAZINYL COMPOUNDS<br/>[FR] NOUVEAUX COMPOSES D'ARYLPIPERAZINYLE
  申请人：PREDIX PHARMACEUTICALS HOLDING

  公开号：WO2004069794A3

  公开（公告）日：2004-11-04
• NEW ARYLPIPERAZINYL COMPOUNDS
  申请人：Predix Pharmaceuticals Holdings, Inc.

  公开号：EP1592425A2

  公开（公告）日：2005-11-09
• EP1592425A4
  申请人：——

  公开号：EP1592425A4

  公开（公告）日：2007-01-24