N-(5-(tert-butyl)isoxazol-3-yl)-N'-(4-(imidazo[1,2-b]pyridazin-2-yl)phenyl)urea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-(5-(tert-butyl)isoxazol-3-yl)-N'-(4-(imidazo[1,2-b]pyridazin-2-yl)phenyl)urea
• 英文别名: 1-(5-Tert-butyl-1,2-oxazol-3-yl)-3-(4-imidazo[1,2-b]pyridazin-2-ylphenyl)urea；1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(4-imidazo[1,2-b]pyridazin-2-ylphenyl)urea
• 化学式: C₂₀H₂₀N₆O₂
• 分子量: 376.418
• InChiKey: AUKRZCMJIRLRPT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  97.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-溴-4'-硝基苯乙酮 在 铁粉 、 氯化铵 作用下， 以 乙醇 、 氯仿 、 水 为溶剂， 反应 3.0h， 生成 N-(5-(tert-butyl)isoxazol-3-yl)-N'-(4-(imidazo[1,2-b]pyridazin-2-yl)phenyl)urea
  参考文献：
  名称：

  Discovery of novel N-(5-(tert-butyl)isoxazol-3-yl)-N′-phenylurea analogs as potent FLT3 inhibitors and evaluation of their activity against acute myeloid leukemia in vitro and in vivo

  摘要：

  FLT3 inhibitors have been explored as a viable therapy for acute myeloid leukemia (AML). However, the clinical outcomes of these FLT3 inhibitors were underwhelming except AC220. Therefore, the development of novel FLT3 inhibitors with high potency against both FLT3-WT and FLT3-ITD mutants are strongly demanded at the present time. In this study, we designed and synthesized a series of novel N-(5-(tert-butyl) isoxazol-3-yl)-N'-phenylurea derivatives as FLT3 inhibitors. SAR studies focused on the fused rings led to the discovery of a series of compounds with high potency against FLT3-ITD-bearing MV4-11 cells and significantly inhibitory activity toward FLT3. Among these compounds, N-(5-(tert-butyl) isoxazol-3-yl)-N'-(4-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl) urea (16i), displayed acceptable aqueous solubility, desirable pharmacokinetic profile and high cytotoxicity selectivity against MV4-11 cells. This compound can inhibit phosphorylation of FLT3 and induce apoptosis in a concentration-dependent manner. Further in vivo antitumor studies showed that 16i led to complete tumor regression in the MV4-11 xenograft model at a dose of 60 mg/kg/d while without observable body weight loss. This study had provided us a new chemotype of FLT3 inhibitors as novel therapic candidates for AML. (C) 2015 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2015.06.033

文献信息

• Discovery of novel N-(5-(tert-butyl)isoxazol-3-yl)-N′-phenylurea analogs as potent FLT3 inhibitors and evaluation of their activity against acute myeloid leukemia in vitro and in vivo
  作者：Ying Xu、Ning-Yu Wang、Xue-Jiao Song、Qian Lei、Ting-Hong Ye、Xin-Yu You、Wei-Qiong Zuo、Yong Xia、Li-Dan Zhang、Luo-Ting Yu

  DOI：10.1016/j.bmc.2015.06.033

  日期：2015.8

  FLT3 inhibitors have been explored as a viable therapy for acute myeloid leukemia (AML). However, the clinical outcomes of these FLT3 inhibitors were underwhelming except AC220. Therefore, the development of novel FLT3 inhibitors with high potency against both FLT3-WT and FLT3-ITD mutants are strongly demanded at the present time. In this study, we designed and synthesized a series of novel N-(5-(tert-butyl) isoxazol-3-yl)-N'-phenylurea derivatives as FLT3 inhibitors. SAR studies focused on the fused rings led to the discovery of a series of compounds with high potency against FLT3-ITD-bearing MV4-11 cells and significantly inhibitory activity toward FLT3. Among these compounds, N-(5-(tert-butyl) isoxazol-3-yl)-N'-(4-(7-methoxyimidazo[1,2-a]pyridin-2-yl)phenyl) urea (16i), displayed acceptable aqueous solubility, desirable pharmacokinetic profile and high cytotoxicity selectivity against MV4-11 cells. This compound can inhibit phosphorylation of FLT3 and induce apoptosis in a concentration-dependent manner. Further in vivo antitumor studies showed that 16i led to complete tumor regression in the MV4-11 xenograft model at a dose of 60 mg/kg/d while without observable body weight loss. This study had provided us a new chemotype of FLT3 inhibitors as novel therapic candidates for AML. (C) 2015 Published by Elsevier Ltd.