Boc-D-Tic-D-p-Cl-Phe-OH | 252008-71-2

• 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: Boc-D-Tic-D-p-Cl-Phe-OH
• 英文别名: (N-tert-butoxycarbonyl-D-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4-chloro-D-phenylalanine；N-Boc-(R)-Tic-(R)-(4-Cl)Phe-OH；Boc-D-Tic-D-(4-Cl)Phe-OH；Boc-D-Tic-D-Phe(4-Cl)-OH；(2R)-3-(4-chlorophenyl)-2-[[(3R)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]propanoic acid
• CAS: 252008-71-2
• 化学式: C₂₄H₂₇ClN₂O₅
• 分子量: 458.942
• InChiKey: QPPVJYFVJCJKTP-WOJBJXKFSA-N

物化性质

• 沸点：
  672.8±55.0 °C(Predicted)
• 密度：
  1.291±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  95.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  Boc-D-Tic-D-p-Cl-Phe-OH 在 双氧水 、 溶剂黄146 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 1-[(D-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4-chloro-D-phenylalanyl]-4-oxy-4-phenylpiperazine ditrifluoroacetate
  参考文献：
  名称：

  新的取代哌嗪作为黑皮质素受体的配体。与“ THIQ”的X射线结构相关。

  摘要：

  合成了一系列黑皮质素4受体（MC4R）特异性小分子激动剂“ THIQ”的哌嗪类似物，并在结构和药理上进行了表征。首先，准备了一些缺少三唑部分的THIQ仿制品。合成包括4-苯基哌嗪或4-环己基哌嗪的酰化。在两种情况下，叔胺官能团被相应的N-氧化物代替。为了获得更复杂的结构，通过用N，N-双（2-氯乙基）苄胺烷基化环己烷衍生的氨基醇的伯氨基，形成4-取代的哌嗪环。首先用甲磺酰氯活化中间体的羟基，然后将原位形成的磺酸酯与1,2,4-三唑的钠盐引入反应中。在一种情况下（即，制备23c）在环己烷环的碳上引入1,2,4-三唑部分。另外，该中间体含有通过其氮原子与反应中心附近的环己烷环碳连接的哌嗪部分。如本文的NMR和X射线研究中所确定的，该取代在保留1，2-二取代的环己烷的初始反式构型的情况下进行。为了获得23c的纯对映异构体，将其前体21c在Chirobiotic V柱上进行手性色谱法。将获得的衍生

  DOI：

  10.1021/jm0311285
• 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 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 Boc-D-Tic-D-p-Cl-Phe-OH
  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

• Melanocortin receptor ligands
  申请人：——

  公开号：US20020072604A1

  公开（公告）日：2002-06-13

  A compound of the formula 1 wherein R 3 , R 4 , R 6 , R 7 , X 4 , Q and HET are as defined above, useful for the treatment or prevention of disorders, diseases or conditions responsive to the activation of melanocortin receptor.

  一种化合物，其化学式为1，其中R3、R4、R6、R7、X4、Q和HET的定义如上所述，用于治疗或预防对黑色素细胞激素受体激活敏感的疾病、疾病或病情。
• 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.
• WO2006/133098
  申请人：——

  公开号：——

  公开（公告）日：——
• Privileged structure-based ligands for melanocortin receptors—tetrahydroquinolines, indoles, and aminotetralines
  作者：Matthew J. Fisher、Ryan T. Backer、Saba Husain、Hansen M. Hsiung、Jeffrey T. Mullaney、Thomas P. O’Brian、Paul L. Ornstein、Roger R. Rothhaar、John M. Zgombick、Karin Briner

  DOI：10.1016/j.bmcl.2005.07.035

  日期：2005.10

  Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1. Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1. (c) 2005 Elsevier Ltd. All rights reserved.
• Privileged structure based ligands for melanocortin-4 receptors—Aliphatic piperazine derivatives
  作者：Karin Briner、Iván Collado、Matthew J. Fisher、Cristina García-Paredes、Saba Husain、Steven L. Kuklish、Ana I. Mateo、Thomas P. O’Brien、Paul L. Ornstein、John Zgombick、Óscar de Frutos

  DOI：10.1016/j.bmcl.2006.04.002

  日期：2006.7

  Aliphatic carbocyclic replacement of the benzyl group of compound I yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R. (c) 2006 Elsevier Ltd. All rights reserved.