Benzyl 4-[2-[(2-thiophen-2-ylethylamino)methyl]phenyl]piperazine-1-carboxylate | 626220-82-4

• 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: Benzyl 4-[2-[(2-thiophen-2-ylethylamino)methyl]phenyl]piperazine-1-carboxylate
• CAS: 626220-82-4
• 化学式: C₂₅H₂₉N₃O₂S
• 分子量: 435.59
• InChiKey: QCRXANLFJUNUHK-UHFFFAOYSA-N

物化性质

• 沸点：
  601.1±55.0 °C(Predicted)
• 密度：
  1.211±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  73
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Benzyl 4-[2-[(2-thiophen-2-ylethylamino)methyl]phenyl]piperazine-1-carboxylate 在 palladium on activated charcoal 氨 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 二乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 50.0h， 生成 4-[(2R)-amino-3-(2,4-dichlorophenyl)propionyl]-1-{2-[N-Boc-(2-thienyl)ethylaminomethyl]phenyl}piperazine
  参考文献：
  名称：

  4-{(2R)-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl}-1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a Potent and Selective Melanocortin-4 Receptor AntagonistDesign, Synthesis, and Characterization

  摘要：

  Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure-activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K-i value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 muM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.

  DOI：

  10.1021/jm049278i
• 作为产物：
  描述：

  苄基-1-哌嗪碳酸酯 在 三乙酰氧基硼氢化钠 、 potassium carbonate 作用下， 以 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 35.0h， 生成 Benzyl 4-[2-[(2-thiophen-2-ylethylamino)methyl]phenyl]piperazine-1-carboxylate
  参考文献：
  名称：

  A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice

  摘要：

  Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (K-i > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (K-i = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.03.053

文献信息

• Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor
  作者：Joseph Pontillo、Joseph A. Tran、Beth A. Fleck、Dragan Marinkovic、Melissa Arellano、Fabio C. Tucci、Marion Lanier、Jodie Nelson、Jessica Parker、John Saunders、Brian Murphy、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmcl.2004.08.055

  日期：2004.11

  SAR studies of a series of piperazinebenzylamines resulted in the discovery of potent antagonists of the human melanocortin-4 receptor. Compounds 11c, 11d, and 11l, which had K-i values of 21, 14, and 15 nM, respectively, possessed low efficacy in cAMP stimulation (similar to15% of alpha-MSH maximal level) mediated by MC4R, and functioned as antagonists in inhibition of alpha-MSH-stimulated cAMP release in a dose-dependent manner (11l, IC50 = 36 nM). (C) 2004 Elsevier Ltd. All rights reserved.
• 4-{(<i>2R</i>)-[3-Aminopropionylamido]-3-(2,4-dichlorophenyl)propionyl}-1-{2-[(2-thienyl)ethylaminomethyl]phenyl}piperazine as a Potent and Selective Melanocortin-4 Receptor AntagonistDesign, Synthesis, and Characterization
  作者：Chen、Joseph Pontillo、Beth A. Fleck、Yinghong Gao、Jenny Wen、Joe A. Tran、Fabio C. Tucci、Dragan Marinkovic、Alan C. Foster、John Saunders

  DOI：10.1021/jm049278i

  日期：2004.12.1

  Recent studies have demonstrated that melanocortin-4 receptor (MC4R) antagonists can prevent weight loss in tumor-bearing mice, which indicates clinical usage for the treatment of cachexia. In our efforts to develop potent and selective antagonists of the human MC4R, we designed piperazinebenzylamines bearing a 2,4-dichlorophenylalanine, by utilizing information derived from structure-activity relationships of MC4R agonists and mutagenesis results of the MC4R and peptide ligands. On the basis of known MC4R agonists such 6, we successfully synthesized potent MC4R antagonists exemplified by 10, which possesses a K-i value of 1.8 nM in binding affinity. 10 does not stimulate cAMP release in HEK 293 cells expressing the human MC4 receptor at 10 muM concentration. It was demonstrated by Schild analysis that 10 was a competitive functional antagonist with a pA(2) value of 7.9 in the inhibition of alpha-MSH-stimulated cAMP accumulation. 10 also penetrated into the brain when dosed intravenously in rats.
• A potent and selective nonpeptide antagonist of the melanocortin-4 receptor induces food intake in satiated mice
  作者：Joseph Pontillo、Joseph A. Tran、Stacy Markison、Margaret Joppa、Beth A. Fleck、Dragan Marinkovic、Melissa Arellano、Fabio C. Tucci、Marion Lanier、Jodie Nelson、John Saunders、Sam R.J. Hoare、Alan C. Foster、Chen Chen

  DOI：10.1016/j.bmcl.2005.03.053

  日期：2005.5

  Optimization on a series of piperazinebenzylamines resulted in analogues with low nanomolar binding at the human MC4 receptor but weak affinity (K-i > 500 nM) at the MC3 receptor. Compound 14c was identified to be a potent MC4R antagonist (K-i = 3.2 nM) with a selectivity of 240-fold over MC3R. It proved to be an insurmountable antagonist in a cAMP assay. Compound 14c potently stimulated food intake in satiated mice when given by intracerebroventricular administration. (c) 2005 Elsevier Ltd. All rights reserved.