2-bromo-N-(3-trifluoromethoxyphenyl)acetamide | 886796-55-0

• 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: 2-bromo-N-(3-trifluoromethoxyphenyl)acetamide
• 英文别名: 2-Bromo-N-[3-(trifluoromethoxy)phenyl]acetamide
• CAS: 886796-55-0
• 化学式: C₉H₇BrF₃NO₂
• 分子量: 298.059
• InChiKey: WYOYLOQUFCXSEY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-bromo-N-(3-trifluoromethoxyphenyl)acetamide 、 苦豆碱 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 12N-(N'-(m-trifluoromethoxyphenyl)carbamoylmethyl)aloperine
  参考文献：
  名称：

  12种N-取代山坡碱衍生物通过蛋白酶体途径作为PD-L1下调剂的构效关系及生物学评价

  摘要：

  作为我们工作的继续，我们合成了29 个 12  N-取代的 aloperine 衍生物，并筛选了其对 H460 细胞中 PD-L1 表达的抑制作用。系统的结构修饰导致化合物6b被鉴定为最活跃的 PD-L1 调节剂。化合物6b在 20 μM 浓度下可显着下调 NSCLC 细胞中组成型和诱导型 PD-L1 的表达，并依次增强共培养 T 细胞对肿瘤细胞的细胞毒性。此外，它对 Lewis 肿瘤异种移植物表现出中等的体内抗癌功效，具有稳定的 PK 和安全性。机理研究表明，6b通过蛋白酶体途径而不是溶酶体途径介导PD-L1的降解。这些结果通过靶向PD-L1激活免疫细胞杀死癌细胞，为具有独特内环骨架的aloperine衍生物的癌症免疫治疗提供了强有力的信息。

  DOI：

  10.1016/j.bioorg.2021.105432
• 作为产物：
  描述：

  溴乙酰氯 、 3-三氟甲氧基苯胺 在 sodium hydroxide 作用下， 以 二氯甲烷 为溶剂， 生成 2-bromo-N-(3-trifluoromethoxyphenyl)acetamide
  参考文献：
  名称：

  Discovery of 3-Methyl-N-(1-oxy-3‘,4‘,5‘,6‘-tetrahydro-2‘H-[2,4‘-bipyridine]-1‘-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D₄ Agonist for the Treatment of Erectile Dysfunction

  摘要：

  The goal of this study was to identify a structurally distinct D-4-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl) piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl) piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.

  DOI：

  10.1021/jm060662k

文献信息

• Discovery of 3-Methyl-<i>N</i>-(1-oxy-3‘,4‘,5‘,6‘-tetrahydro-2‘<i>H</i>-[2,4‘-bipyridine]-1‘-ylmethyl)benzamide (ABT-670), an Orally Bioavailable Dopamine D₄ Agonist for the Treatment of Erectile Dysfunction
  作者：Meena V. Patel、Teodozyj Kolasa、Kathleen Mortell、Mark A. Matulenko、Ahmed A. Hakeem、Jeffrey J. Rohde、Sherry L. Nelson、Marlon D. Cowart、Masaki Nakane、Loan N. Miller、Marie E. Uchic、Marc A. Terranova、Odile F. El-Kouhen、Diana L. Donnelly-Roberts、Marian T. Namovic、Peter R. Hollingsworth、Renjie Chang、Brenda R. Martino、Jill M. Wetter、Kennan C. Marsh、Ruth Martin、John F. Darbyshire、Gary Gintant、Gin C. Hsieh、Robert B. Moreland、James P. Sullivan、Jorge D. Brioni、Andrew O. Stewart

  DOI：10.1021/jm060662k

  日期：2006.12.1

  The goal of this study was to identify a structurally distinct D-4-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl) piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl) piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
• Structure–activity relationship and biological evaluation of 12 N-substituted aloperine derivatives as PD-L1 down-regulatory agents through proteasome pathway
  作者：Qing–Xuan Zeng、Kun Wang、Xin Zhang、Yu-Long Shi、Yue–Ying Dou、Zhi–Hao Guo、Xin–Tong Zhang、Na Zhang、Hong–Bin Deng、Ying–Hong Li、Dan–Qing Song

  DOI：10.1016/j.bioorg.2021.105432

  日期：2021.12

  aloperine derivatives were synthesized and screened for suppression on PD-L1 expression in H460 cells, as a continuation of our work. Systematic structural modifications led to the identification of compound 6b as the most active PD-L1 modulator. Compound 6b could significantly down-regulate both constitutive and inductive PD-L1 expression in NSCLC cells, and successively enhance the cytotoxicity of co-cultured

  作为我们工作的继续，我们合成了29 个 12  N-取代的 aloperine 衍生物，并筛选了其对 H460 细胞中 PD-L1 表达的抑制作用。系统的结构修饰导致化合物6b被鉴定为最活跃的 PD-L1 调节剂。化合物6b在 20 μM 浓度下可显着下调 NSCLC 细胞中组成型和诱导型 PD-L1 的表达，并依次增强共培养 T 细胞对肿瘤细胞的细胞毒性。此外，它对 Lewis 肿瘤异种移植物表现出中等的体内抗癌功效，具有稳定的 PK 和安全性。机理研究表明，6b通过蛋白酶体途径而不是溶酶体途径介导PD-L1的降解。这些结果通过靶向PD-L1激活免疫细胞杀死癌细胞，为具有独特内环骨架的aloperine衍生物的癌症免疫治疗提供了强有力的信息。