N-[4'-[1-hydroxy(1H-imidazol-4-yl)methyl][1,1'-biphenyl]-3-yl]acetamide | 1293981-09-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-[4'-[1-hydroxy(1H-imidazol-4-yl)methyl][1,1'-biphenyl]-3-yl]acetamide
• 英文别名: rac-N-[4''-[1-Hydroxy(1H-imidazol-4-yl)methyl][1,1''-biphenyl]-3-yl]acetamide；N-[3-[4-[hydroxy(1H-imidazol-5-yl)methyl]phenyl]phenyl]acetamide
• CAS: 1293981-09-5
• 化学式: C₁₈H₁₇N₃O₂
• 分子量: 307.352
• InChiKey: YKJRYOUVLGHMHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  78
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  N-[4'-[(1-trityl-1H-imidazol-4-yl)carbonyl][1,1'-biphenyl]-3-yl]acetamide 在 sodium tetrahydroborate 、 吡啶盐酸盐 作用下， 以 甲醇 为溶剂， 反应 7.0h， 生成 N-[4'-[1-hydroxy(1H-imidazol-4-yl)methyl][1,1'-biphenyl]-3-yl]acetamide
  参考文献：
  名称：

  17,20-裂解酶抑制剂。第3部分：作为新型17,20-裂解酶抑制剂的联苯基甲基甲基咪唑衍生物的设计，合成和结构-活性关系

  摘要：

  合成了一系列新颖的联苯甲酰基甲基咪唑衍生物和相关化合物，作为类固醇激素生产中的关键酶17,20-裂合酶的抑制剂，并对其生物学活性进行了评估。为了确定17,20-裂解酶对相关CYP3A4酶的有效和选择性抑制剂，使用哺乳动物CYP2C5酶的X射线晶体学结构开发了人17,20-裂解酶的同源性模型。借助分子建模，对联苯部分进行了优化，得到了乙酰胺衍生物，将其通过HPLC拆分，得到了活性（-）-对映异构体。所获得的活性对映异构体不仅显示出对大鼠和人的17,20-裂合酶均具有有效的抑制作用，且IC 50值分别为14和26 nM，但对CYP3A4抑制17,20-裂解酶的选择性也极好（> 300倍）。此外，单只口服给药后，该活性对映异构体可显着降低猴子模型中的血清睾丸激素和DHEA浓度。活性对映体的不对称合成也通过使用非对映选择性格氏反应的手性中间体进行。

  DOI：

  10.1016/j.bmc.2011.02.009

文献信息

• PHARMACOPHORES, COMPOUNDS AND METHODS HAVING APPLICATION IN THE TREATMENT OF CANCER THROUGH INHIBITION OF CYP17A1 AND CYP19A1
  申请人：MANGOSUTHU UNIVERSITY OF TECHNOLOGY

  公开号：US20200247794A1

  公开（公告）日：2020-08-06

  The invention provides pharmacophores for use in the design, screening and identification of inhibitors of CYP17A1 and CYP19A1 enzymes. A preferred pharmacophore has a spatial arrangement of atoms as shown in the accompanying FIG. 1 , wherein: ●A represents hydrogen bond acceptors; ●D represents hydrogen bond donors; and ●R represents aromatic rings. Compounds conforming to the preferred pharmacophore are provided for use as medicaments in the treatment of cancer, especially prostate cancer and breast cancer. By way of example, these compounds include N-(4-ethylphenyl)-5-(2-hydroxy-5-methoxybenzoyl)-2-imino-2H-pyran-3-carboxamide and 2-(4-sulfamoylphenoxy) ethyl 2-amino-3-methylbenzoate. Also provided are methods for the treatment of prostate cancer and breast cancer using the compounds of the invention as well as their salts, solvates, hydrates, primary metabolites and prodrugs. Methods of inhibiting CYP17A1 and CYP19A1, and hence of inhibiting androgen activity in a subject, are disclosed. The invention also provides processes for designing, screening and identifying compounds which can inhibit CYP17A1 and CYP19A1.
• 17,20-Lyase inhibitors. Part 3: Design, synthesis, and structure–activity relationships of biphenylylmethylimidazole derivatives as novel 17,20-lyase inhibitors
  作者：Tomohiro Kaku、Saori Tsujimoto、Nobuyuki Matsunaga、Toshimasa Tanaka、Takahito Hara、Masuo Yamaoka、Masami Kusaka、Akihiro Tasaka

  DOI：10.1016/j.bmc.2011.02.009

  日期：2011.4

  A novel series of biphenylylmethylimidazole derivatives and related compounds were synthesized as inhibitors of 17,20-lyase, a key enzyme in the production of steroid hormones, and their biological activities were evaluated. In an attempt to identify potent and selective inhibitors of 17,20-lyase over the related CYP3A4 enzyme, a homology model for human 17,20-lyase was developed using the X-ray crystallographic

  合成了一系列新颖的联苯甲酰基甲基咪唑衍生物和相关化合物，作为类固醇激素生产中的关键酶17,20-裂合酶的抑制剂，并对其生物学活性进行了评估。为了确定17,20-裂解酶对相关CYP3A4酶的有效和选择性抑制剂，使用哺乳动物CYP2C5酶的X射线晶体学结构开发了人17,20-裂解酶的同源性模型。借助分子建模，对联苯部分进行了优化，得到了乙酰胺衍生物，将其通过HPLC拆分，得到了活性（-）-对映异构体。所获得的活性对映异构体不仅显示出对大鼠和人的17,20-裂合酶均具有有效的抑制作用，且IC 50值分别为14和26 nM，但对CYP3A4抑制17,20-裂解酶的选择性也极好（> 300倍）。此外，单只口服给药后，该活性对映异构体可显着降低猴子模型中的血清睾丸激素和DHEA浓度。活性对映体的不对称合成也通过使用非对映选择性格氏反应的手性中间体进行。