C-cyclohexyl-N-methyl-N-{4-[4-(3-nitrophenyl)piperazin-1-yl]butyl}methanesulfonamide | 740873-23-8

• 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: C-cyclohexyl-N-methyl-N-{4-[4-(3-nitrophenyl)piperazin-1-yl]butyl}methanesulfonamide
• 英文别名: 1-cyclohexyl-N-methyl-N-[4-[4-(3-nitrophenyl)piperazin-1-yl]butyl]methanesulfonamide
• CAS: 740873-23-8
• 化学式: C₂₂H₃₆N₄O₄S
• 分子量: 452.618
• InChiKey: YBFQAMAAWZIYMQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  98.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  C-cyclohexyl-N-methyl-N-{4-[4-(3-nitrophenyl)piperazin-1-yl]butyl}methanesulfonamide 在 盐酸 、 三乙胺 、 tin(ll) chloride 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 0.5h， 生成 N-(3-{4-[4-(cyclohexylmethanesulfonylmethylamino)butyl]piperazin-1-yl}phenyl)acetamide
  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：

  环己基甲烷磺酰氯 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 51.0h， 生成 C-cyclohexyl-N-methyl-N-{4-[4-(3-nitrophenyl)piperazin-1-yl]butyl}methanesulfonamide
  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：Dhanoa S. Dale

  公开号：US20070004742A1

  公开（公告）日：2007-01-04

  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.

  本发明涉及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，用于治疗由5-HT受体直接或间接介导的疾病。这些疾病包括中枢神经系统疾病，如广泛性焦虑症、注意力缺陷/多动障碍、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
• US7491727B2
  申请人：——

  公开号：US7491727B2

  公开（公告）日：2009-02-17
• US7488731B2
  申请人：——

  公开号：US7488731B2

  公开（公告）日：2009-02-10