(R)-3-[(R)-1-(4-Chloro-benzyl)-2-oxo-2-(4-o-tolyl-piperazin-1-yl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester | 444583-66-8

• 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: (R)-3-[(R)-1-(4-Chloro-benzyl)-2-oxo-2-(4-o-tolyl-piperazin-1-yl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
• CAS: 444583-66-8
• 化学式: C₃₅H₄₁ClN₄O₄
• 分子量: 617.188
• InChiKey: NNTDSWRBYPWQQV-BVRKHOPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.39
• 重原子数：
  44.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  82.19
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 (R)-3-[(R)-1-(4-Chloro-benzyl)-2-oxo-2-(4-o-tolyl-piperazin-1-yl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 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-oxo-2-(4-o-tolyl-piperazin-1-yl)-ethyl]-amide; compound with trifluoro-acetic acid
  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
• 作为产物：
  描述：

  D-对氯苯丙氨酸甲酯 在 4-二甲氨基吡啶 、 sodium hydroxide 、 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 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-) 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-3-[(R)-1-(4-Chloro-benzyl)-2-oxo-2-(4-o-tolyl-piperazin-1-yl)-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
  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