N-((1S)-[2-{4-[(2R)-amino-3-(2,4-dichlorophenyl)propionyl]-1-piperazinyl}-3-fluorophenyl]-3-methylbutyl)-(S)-tert-butanesulfinamide | 943521-69-5

• 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-((1S)-[2-{4-[(2R)-amino-3-(2,4-dichlorophenyl)propionyl]-1-piperazinyl}-3-fluorophenyl]-3-methylbutyl)-(S)-tert-butanesulfinamide
• 英文别名: (S)-N-[(1S)-1-[2-[4-[(2R)-2-amino-3-(2,4-dichlorophenyl)propanoyl]piperazin-1-yl]-3-fluorophenyl]-3-methylbutyl]-2-methylpropane-2-sulfinamide
• CAS: 943521-69-5
• 化学式: C₂₈H₃₉Cl₂FN₄O₂S
• 分子量: 585.614
• InChiKey: OROAPARMHOHPOO-WLAGNTMJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  38
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  97.9
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-((1S)-[2-{4-[(2R)-amino-3-(2,4-dichlorophenyl)propionyl]-1-piperazinyl}-3-fluorophenyl]-3-methylbutyl)-(S)-tert-butanesulfinamide 在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 生成 N-[(2R)-1-[4-[2-[(1S)-1-amino-3-methylbutyl]-6-fluorophenyl]piperazin-1-yl]-3-(2,4-dichlorophenyl)-1-oxopropan-2-yl]acetamide
  参考文献：
  名称：

  Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity

  摘要：

  A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.05.026
• 作为产物：
  描述：

  N-((1S)-[2-{4-[(2R)-(tert-butoxycarbonylamino)-3-(2,4-dichlorophenyl)propionyl]-1-piperazinyl}-3-fluorophenyl]-3-methylbutyl)-(S)-tert-butanesulfinamide 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 N-((1S)-[2-{4-[(2R)-amino-3-(2,4-dichlorophenyl)propionyl]-1-piperazinyl}-3-fluorophenyl]-3-methylbutyl)-(S)-tert-butanesulfinamide
  参考文献：
  名称：

  Design, Synthesis, In Vitro, and In Vivo Characterization of Phenylpiperazines and Pyridinylpiperazines as Potent and Selective Antagonists of the Melanocortin-4 Receptor

  摘要：

  Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K-i value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.

  DOI：

  10.1021/jm701137s

文献信息

• [EN] LIGANDS OF MELANOCORTIN RECEPTORS AND COMPOSITIONS AND METHODS RELATED THERETO<br/>[FR] LIGANDS DE RECEPTEURS DE LA MELANOCORTINE, COMPOSITIONS ET PROCEDES ASSOCIES
  申请人：NEUROCRINE BIOSCIENCES INC

  公开号：WO2005042516A3

  公开（公告）日：2005-12-01
• Design, Synthesis, In Vitro, and In Vivo Characterization of Phenylpiperazines and Pyridinylpiperazines as Potent and Selective Antagonists of the Melanocortin-4 Receptor
  作者：Joe A. Tran、Wanlong Jiang、Fabio C. Tucci、Beth A. Fleck、Jenny Wen、Yang Sai、Ajay Madan、Ta Kung Chen、Stacy Markison、Alan C. Foster、Sam R. Hoare、Daniel Marks、John Harman、Caroline W. Chen、Melissa Arellano、Dragan Marinkovic、Haig Bozigian、John Saunders、Chen Chen

  DOI：10.1021/jm701137s

  日期：2007.12.13

  Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K-i value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
• Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity
  作者：Joe A. Tran、Fabio C. Tucci、Wanlong Jiang、Dragan Marinkovic、Caroline W. Chen、Melissa Arellano、Stacy Markison、Beth A. Fleck、Jenny Wen、Nicole S. White、Joseph Pontillo、John Saunders、Daniel Marks、Sam R. Hoare、Ajay Madan、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmc.2007.05.026

  日期：2007.8

  A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model. (c) 2007 Elsevier Ltd. All rights reserved.