1-(D-Tic-4-Cl-D-Phe)-4-(2-ethoxyphenyl)piperazine trifluoroacetic acid salt

• 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: 1-(D-Tic-4-Cl-D-Phe)-4-(2-ethoxyphenyl)piperazine trifluoroacetic acid salt
• 化学式: C₂HF₃O₂*C₃₁H₃₅ClN₄O₃
• 分子量: 661.121
• InChiKey: BBWTWKLLVMWAII-CNZCJKERSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.46
• 重原子数：
  46.0
• 可旋转键数：
  8.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  111.21
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  1-(2-乙氧基苯基)哌嗪 在 N-羟基-7-氮杂苯并三氮唑 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 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 1.0h， 生成 1-(D-Tic-4-Cl-D-Phe)-4-(2-ethoxyphenyl)piperazine trifluoroacetic acid salt
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of Novel Arylpiperazines as Potent and Selective Agonists of the Melanocortin Subtype-4 Receptor

  摘要：

  The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-D-Tic-D-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K-i = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K-i = 6600 nM). Sulfonamide 39 (K-i = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K-i = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K-i = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.

  DOI：

  10.1021/jm0304109

文献信息

• Synthesis and Structure−Activity Relationships of Novel Arylpiperazines as Potent and Selective Agonists of the Melanocortin Subtype-4 Receptor
  作者：Timothy I. Richardson、Paul L. Ornstein、Karin Briner、Matthew J. Fisher、Ryan T. Backer、C. Kelly Biggers、Michael P. Clay、Paul J. Emmerson、Larry W. Hertel、Hansen M. Hsiung、Saba Husain、Steven D. Kahl、Jonathan A. Lee、Terry D. Lindstrom、Michael J. Martinelli、John P. Mayer、Jeffery T. Mullaney、Thomas P. O'Brien、Joseph M. Pawlak、Kevin D. Revell、Jikesh Shah、John M. Zgombick、R. Jason Herr、Alex Melekhov、Peter B. Sampson、Chi-Hsin R. King

  DOI：10.1021/jm0304109

  日期：2004.1.1

  The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-D-Tic-D-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K-i = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K-i = 6600 nM). Sulfonamide 39 (K-i = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K-i = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K-i = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.