A2-CAR-3 | 1402793-73-0

• 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: A2-CAR-3
• 英文别名: (4-nitrophenyl) N-[3-[[2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino]phenyl]carbamate
• CAS: 1402793-73-0
• 化学式: C₂₃H₂₅N₇O₄
• 分子量: 463.496
• InChiKey: KIEOBULVOHCTQX-UHFFFAOYSA-N

物化性质

• 沸点：
  642.4±55.0 °C(Predicted)
• 密度：
  1.369±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  128
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  A2-CAR-3 、 2-氯-5-氨基三氟甲苯 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-ylamino)phenyl)urea
  参考文献：
  名称：

  Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

  摘要：

  V‐RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4‐phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non‐small‐cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG‐out conformation of BRAF.

  DOI：

  10.1111/cbdd.12198
• 作为产物：
  描述：

  2-methyl-6-(4-methylpiperazin-1-yl)-N-(3-nitrophenyl)pyrimidin-4-amine 在 铁粉 、 氯化铵 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 5.5h， 生成 A2-CAR-3
  参考文献：
  名称：

  Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores

  摘要：

  V‐RAF murine sarcoma viral oncogene homologue B1 (BRAF) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS/RAF/MEK/ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4‐phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non‐small‐cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG‐out conformation of BRAF.

  DOI：

  10.1111/cbdd.12198

文献信息

• Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments
  作者：Qingwen Zhang、Xuejin Zhang、Qidong You

  DOI：10.3390/molecules21070879

  日期：——

  of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions. Data recently obtained with structurally validated type II inhibitors supported the conclusion that type II inhibitors are more selective than type I inhibitors. In our type II BRAF V600E inhibitor lead discovery effort, we identified phenylaminopyrimidine (PAP) and

  第一个获批的激酶抑制剂伊马替尼的成功激发了人们对开发靶向非活性DFG-out构象的II型抑制剂的极大兴趣，其中在激活环起点的DFG基序的Phe指向ATP结合位点。然而，到目前为止，已启动的激酶抑制剂在靶向活性DFG-in构象的I型抑制剂中有很大的偏向，其中DFG基序的Phe相对于非活性构象翻转约180°，导致Phe和Asp交换位置。最近通过结构验证的II型抑制剂获得的数据支持以下结论：II型抑制剂比I型抑制剂更具选择性。在我们的II型BRAF V600E抑制剂领先发现工作中，我们将苯氨基嘧啶（PAP）和不对称双取代尿素鉴定为两个在FDA批准的蛋白激酶抑制剂中经常出现的片段。因此，我们将PAP和不对称双取代尿素定义为激酶药物发现的优先片段。基于这些特权片段，组装了II型抑制剂的药效基团4-苯基氨基嘧啶尿素（4-PAPU）。通过初步的构效关系（SAR）研究，又获得了具有与模板化合物索拉非尼相当的BRAF