4-{(2R)-[(3R)-1,2,3,4-tetrahydroisoquinolinylcarboxamido]-3-(4-chlorophenyl)propionyl}-1-[2-formylphenyl]piperazine | 748808-82-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 4-{(2R)-[(3R)-1,2,3,4-tetrahydroisoquinolinylcarboxamido]-3-(4-chlorophenyl)propionyl}-1-[2-formylphenyl]piperazine
• CAS: 748808-82-4
• 化学式: C₃₅H₃₉ClN₄O₅
• 分子量: 631.171
• InChiKey: QJIRGUDDYAXISE-BVRKHOPBSA-N

物化性质

• 沸点：
  848.6±65.0 °C(Predicted)
• 密度：
  1.275±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.89
• 重原子数：
  45.0
• 可旋转键数：
  7.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  99.26
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  4-{(2R)-[(3R)-1,2,3,4-tetrahydroisoquinolinylcarboxamido]-3-(4-chlorophenyl)propionyl}-1-[2-formylphenyl]piperazine 在 三乙酰氧基硼氢化钠 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 (R)-1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid {(R)-1-(4-chloro-benzyl)-2-[4-(2-diethylaminomethyl-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-amide
  参考文献：
  名称：

  Structure–activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor

  摘要：

  SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a K-i of 11nNL and 13g exhibited an EC50 of 3.8nM and a Ki of 6.4nNL (C) 2004 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2004.06.059
• 作为产物：
  描述：

  1-Boc-4-(2-甲酰苯基)哌嗪 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 4-{(2R)-[(3R)-1,2,3,4-tetrahydroisoquinolinylcarboxamido]-3-(4-chlorophenyl)propionyl}-1-[2-formylphenyl]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