methyl (E)-3-(1-(3-(dimethylamino)-2,2-dimethylpropyl)-2-(2-(methylthio)ethyl)-1H-benzo[d]imidazol-5-yl)acrylate | 1312574-83-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: methyl (E)-3-(1-(3-(dimethylamino)-2,2-dimethylpropyl)-2-(2-(methylthio)ethyl)-1H-benzo[d]imidazol-5-yl)acrylate
• CAS: 1312574-83-6
• 化学式: C₂₁H₃₁N₃O₂S
• 分子量: 389.562
• InChiKey: AMNDKMMTJCXHNW-CSKARUKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.72
• 重原子数：
  27.0
• 可旋转键数：
  9.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  47.36
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 methyl (E)-3-(1-(3-(dimethylamino)-2,2-dimethylpropyl)-2-(2-(methylthio)ethyl)-1H-benzo[d]imidazol-5-yl)acrylate 在 盐酸羟胺 、 sodium methylate 作用下， 以 甲醇 、 乙腈 为溶剂， 以17 mg的产率得到3-(1-(3-dimethylamino-2,2-dimethylpropyl)-2-(2-methylsulfanylethyl)-1H-benzimidazol-5-yl)-N-hydroxyacrylamide trifluoroacetate
  参考文献：
  名称：

  Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

  摘要：

  A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC I enzyme and COLO 205 cellular IC50), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dos-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

  DOI：

  10.1021/jm2003552
• 作为产物：
  描述：

  反式-4-氯-3-硝基肉桂酸甲酯 在 tin(II) chloride dihdyrate 、 溶剂黄146 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 生成 methyl (E)-3-(1-(3-(dimethylamino)-2,2-dimethylpropyl)-2-(2-(methylthio)ethyl)-1H-benzo[d]imidazol-5-yl)acrylate
  参考文献：
  名称：

  Discovery of (2E)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile

  摘要：

  A series of 3-(1,2-disubstituted-1H-benzimidazol-5-yl)-N-hydroxyacrylamides (1) were designed and synthesized as HDAC inhibitors. Extensive SARs have been established for in vitro potency (HDAC I enzyme and COLO 205 cellular IC50), liver microsomal stability (t(1/2)), cytochrome P450 inhibitory (3A4 IC50), and clogP, among others. These parameters were fine-tuned by carefully adjusting the substituents at positions 1 and 2 of the benzimidazole ring. After comprehensive in vitro and in vivo profiling of the selected compounds, SB939 (3) was identified as a preclinical development candidate. 3 is a potent pan-HDAC inhibitor with excellent druglike properties, is highly efficacious in in vivo tumor models (HCT-116, PC-3, A2780, MV4-11, Ramos), and has high and dos-proportional oral exposures and very good ADME, safety, and pharmaceutical properties. When orally dosed to tumor-bearing mice, 3 is enriched in tumor tissue which may contribute to its potent antitumor activity and prolonged duration of action. 3 is currently being tested in phase I and phase II clinical trials.

  DOI：

  10.1021/jm2003552