ethyl 4-((4-tert-butoxycarbonyl)piperidin-4-yl)phenyl-7-(4-(trifluoromethyl)phenyl)-2-naphthoate | 1160271-34-0

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 英文名称: ethyl 4-((4-tert-butoxycarbonyl)piperidin-4-yl)phenyl-7-(4-(trifluoromethyl)phenyl)-2-naphthoate
• 英文别名: tert-butyl 4-(4-(3-(ethoxycarbonyl)-6-(4-(trifluoromethyl)phenyl)naphthalen-1-yl)phenyl)piperidine-1-carboxylate；tert-butyl 4-(4-{3-(ethoxycarbonyl)-6-[4-(trifluoromethyl)phenyl]-1-naphthyl}phenyl)piperidine-1-carboxylate；tert-butyl 4-[4-[3-ethoxycarbonyl-6-[4-(trifluoromethyl)phenyl]naphthalen-1-yl]phenyl]piperidine-1-carboxylate
• CAS: 1160271-34-0
• 化学式: C₃₆H₃₆F₃NO₄
• 分子量: 603.681
• InChiKey: XYSILUBDUHJJPB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9
• 重原子数：
  44
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 4-((4-tert-butoxycarbonyl)piperidin-4-yl)phenyl-7-(4-(trifluoromethyl)phenyl)-2-naphthoate 在 甲醇 、 sodium carbonate 、 potassium carbonate 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-(Dimethylamino)ethyl 4-(4-piperidin-4-ylphenyl)-7-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylate
  参考文献：
  名称：

  Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y14

  摘要：

  Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile. (C) 2011 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2010.12.113
• 作为产物：
  描述：

  4-(4-溴苯基)哌啶 在 四(三苯基膦)钯 、 potassium carbonate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 ethyl 4-((4-tert-butoxycarbonyl)piperidin-4-yl)phenyl-7-(4-(trifluoromethyl)phenyl)-2-naphthoate
  参考文献：
  名称：

  P2Y14受体杂环拮抗剂的结构指导修饰。

  摘要：

  P2Y14受体（P2Y14R）通过激活嗜中性粒细胞的运动来介导炎症活动，但已知的拮抗剂种类却很少。我们已经研究了3-（4-苯基-1 H-1,2,3-三唑-1-基）-5-（芳基）苯甲酸拮抗剂支架的结构-活性关系，并通过对接和分子动力学来辅助（ MD）在P2Y14R同源性模型上进行仿真。使用高吞吐量MD Python环境的计算管道指导了模拟设计。候选物的选择基于配体-蛋白质的形状和互补性以及配体-蛋白质相互作用随时间的持久性。与噻吩有利地取代5-苯基和在5-芳族和烷基氨基之间插入3-亚甲基间隔基的预测在很大程度上与实验结果一致。核心苯环上的关键羧酸酯基团被四唑取代或5-芳基基团的截短降低了亲和力。使用荧光测定法，最有效的拮抗剂是伯3-氨基丙基同类物20（MRS4458）和苯基对甲酰胺30（MRS4478）。

  DOI：

  10.1021/acs.jmedchem.8b00168

文献信息

• [EN] SUBSTITUTED 2-NAPHTHOIC ACIDS AS ANTAGONISTS OF GPR105 ACTIVITY<br/>[FR] ACIDES 2-NAPHTOÏQUE SUBSTITUÉS EN TANT QU'ANTAGONISTES DE L'ACTIVITÉ DE GPR105
  申请人：MERCK FROSST CANADA LTD

  公开号：WO2009070873A1

  公开（公告）日：2009-06-11

  Substituted 2-naphthoic acids of structural formula I are effective as antagonists of the biological activity of GPR105 protein. They are useful for the treatment, control or prevention of disorders responsive to antagonism of this receptor, such as diabetes, particularly, Type 2 diabetes, insulin resistance, hyperglycemia, lipid disorders, obesity, atherosclerosis, and conditions associated with the Metabolic Syndrome.

  结构式I中的2-萘甲酸替代物对GPR105蛋白的生物活性具有拮抗作用。它们可用于治疗、控制或预防对该受体拮抗有响应的疾病，如糖尿病，特别是2型糖尿病，胰岛素抵抗，高血糖，脂质紊乱，肥胖，动脉粥样硬化以及与代谢综合征相关的疾病。
• SUBSTITUTED 2-NAPHTHOIC ACIDS AS ANTAGONISTS OF GPR105 ACTIVITY
  申请人：Belley Michel

  公开号：US20100298347A1

  公开（公告）日：2010-11-25

  Substituted 2-naphthoic acids of structural formula are effective as antagonists of the biological activity of GPR105 protein. They are useful for the treatment, control or prevention of disorders responsive to antagonism of this receptor, such as diabetes, particularly, Type 2 diabetes, insulin resistance, hyperglycemia, lipid disorders, obesity, atherosclerosis, and conditions associated with the Metabolic Syndrome.

  具有以下结构式的2-萘甲酸替代物是GPR105蛋白生物活性的拮抗剂，对于治疗、控制或预防对此受体的拮抗作用有响应的疾病非常有效，包括糖尿病，特别是2型糖尿病，胰岛素抵抗，高血糖，脂质异常，肥胖症，动脉粥样硬化以及与代谢综合征相关的疾病。
• A Selective High-Affinity Antagonist of the P2Y₁₄ Receptor Inhibits UDP-Glucose–Stimulated Chemotaxis of Human Neutrophils
  作者：Matthew O. Barrett、Juliana I. Sesma、Christopher B. Ball、P. Suresh Jayasekara、Kenneth A. Jacobson、Eduardo R. Lazarowski、T. Kendall Harden

  DOI：10.1124/mol.113.085654

  日期：2013.7

  The nucleotide-sugar–activated P2Y14 receptor (P2Y14-R) is highly expressed in hematopoietic cells. Although the physiologic functions of this receptor remain undefined, it has been strongly implicated recently in immune and inflammatory responses. Lack of availability of receptor-selective high-affinity antagonists has impeded progress in studies of this and most of the eight nucleotide-activated P2Y receptors. A series of molecules recently were identified by Gauthier et al. ([Gauthier et al., 2011][1]) that exhibited antagonist activity at the P2Y14-R. We synthesized one of these molecules, a 4,7-disubstituted 2-naphthoic acid derivative (PPTN), and studied its pharmacological properties in detail. The concentration-effect curve of UDP-glucose for promoting inhibition of adenylyl cyclase in C6 glioma cells stably expressing the P2Y14-R was shifted to the right in a concentration-dependent manner by PPTN. Schild analyses revealed that PPTN-mediated inhibition followed competitive kinetics, with a KB of 434 pM observed. In contrast, 1 μ M PPTN exhibited no agonist or antagonist effect at the P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, or P2Y13 receptors. UDP-glucose–promoted chemotaxis of differentiated HL-60 human promyelocytic leukemia cells was blocked by PPTN with a concentration dependence consistent with the KB determined with recombinant P2Y14-R. In contrast, the chemotactic response evoked by the chemoattractant peptide fMetLeuPhe was unaffected by PPTN. UDP-glucose–promoted chemotaxis of freshly isolated human neutrophils also was blocked by PPTN. In summary, this work establishes PPTN as a highly selective high-affinity antagonist of the P2Y14-R that is useful for interrogating the action of this receptor in physiologic systems. [1]: #ref-15

  1
• Exploration of Alternative Scaffolds for P2Y₁₄ Receptor Antagonists Containing a Biaryl Core
  作者：Young-Hwan Jung、Jinha Yu、Zhiwei Wen、Veronica Salmaso、Tadeusz P. Karcz、Ngan B. Phung、Zhoumou Chen、Sierra Duca、John M. Bennett、Steven Dudas、Daniela Salvemini、Zhan-Guo Gao、Donald N. Cook、Kenneth A. Jacobson

  DOI：10.1021/acs.jmedchem.0c00745

  日期：2020.9.10

  Various heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y(14) receptor (P2Y(14)R) antagonists were synthesized, and affinity was measured in P2Y(14)R-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central m-benzoic acid core (25) provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole. The corresponding P2Y(14)R region is predicted by homology modeling as a deep, sterically limited hydrophobic pocket, with the outward pointing piperidine moiety being the most flexible. Bicyclic-substituted piperidine ring derivatives of naphthalene antagonist 1, e.g., quinuclidine 17 (MRS4608, IC50 approximate to 20 nM at hP2Y(14)R/mP2Y(14)R), or of triazole 2, preserved affinity. Potent antagonists 1, 7a, 17, and 23 (10 mg/kg) protected in an ovalbumin/Aspergillus mouse asthma model, and PEG conjugate 12 reduced chronic pain. Thus, we expanded P2Y(14)R antagonist structure-activity relationship, introducing diverse physical-chemical properties.
• Discovery of a Series of 5-Amide-1<i>H</i>-pyrazole-3-carboxyl Derivatives as Potent P2Y₁₄R Antagonists with Anti-Inflammatory Characters
  作者：Yu-hang Wang、Meng-ze Zhou、Tao Ye、Ping-ping Wang、Ran Lu、Yi-lin Wang、Chun-xiao Liu、Wen Xiao、Jia-yi Li、Zi-bo Meng、Li-li Xu、Qing-hua Hu、Cheng Jiang

  DOI：10.1021/acs.jmedchem.2c01632

  日期：2022.12.8