4-[(2R)-amino-3-(4-chlorophenyl)propionyl]-1-{2-[N-Boc-(2-thienyl)ethylaminomethyl]phenyl}piperazine | 626218-99-3

• 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: 4-[(2R)-amino-3-(4-chlorophenyl)propionyl]-1-{2-[N-Boc-(2-thienyl)ethylaminomethyl]phenyl}piperazine
• 英文别名: tert-butyl N-[[2-[4-[(2R)-2-amino-3-(4-chlorophenyl)propanoyl]piperazin-1-yl]phenyl]methyl]-N-(2-thiophen-2-ylethyl)carbamate
• CAS: 626218-99-3
• 化学式: C₃₁H₃₉ClN₄O₃S
• 分子量: 583.195
• InChiKey: XXJQMZBZYYMFRE-HHHXNRCGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-[(2R)-amino-3-(4-chlorophenyl)propionyl]-1-{2-[N-Boc-(2-thienyl)ethylaminomethyl]phenyl}piperazine 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 N-[(R)-1-(4-Chloro-benzyl)-2-oxo-2-(4-{2-[(2-thiophen-2-yl-ethylamino)-methyl]-phenyl}-piperazin-1-yl)-ethyl]-2-dimethylamino-acetamide
  参考文献：
  名称：

  Piperazinebenzylamines as potent and selective antagonists of the human melanocortin-4 receptor

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2004.08.055
• 作为产物：
  描述：

  噻吩乙胺 在 palladium on activated charcoal 氨 、 氢气 、 三乙酰氧基硼氢化钠 、 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 66.0h， 生成 4-[(2R)-amino-3-(4-chlorophenyl)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

文献信息

• Ligands of melanocortin receptors and compositions and methods related thereto
  申请人：Neurocrine Biosciences, Inc.

  公开号：US20040053933A1

  公开（公告）日：2004-03-18

  Compounds which function as melanocortin receptor ligands and having utility in the treatment of melanocortin receptor-based disorders. The compounds have the following structure (I): 1 including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein Ar, R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 7a , R 7b , q, r, X, Y 1 , Y 2 , Y 3 and Y 4 are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.

  具有在治疗基于黑色素细胞素受体的疾病中有用的功能的化合物。这些化合物具有以下结构（I）：包括立体异构体，前药和其药用可接受的盐，其中Ar，R1，R2，R3a，R3b，R4a，R4b，R5，R7a，R7b，q，r，X，Y1，Y2，Y3和Y4如本文所定义。还公开了含有结构（I）化合物的药物组合物，以及与其使用相关的方法。
• 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.