tert-butyl 3-[4-[(E)-3-methoxy-3-oxoprop-1-enyl]-2-nitroanilino]piperidine-1-carboxylate | 1312574-52-9

• 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: tert-butyl 3-[4-[(E)-3-methoxy-3-oxoprop-1-enyl]-2-nitroanilino]piperidine-1-carboxylate
• CAS: 1312574-52-9
• 化学式: C₂₀H₂₇N₃O₆
• 分子量: 405.451
• InChiKey: AAUNNMANPJDUKO-CSKARUKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-氯-3-硝基肉桂酸 在 硫酸 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 生成 tert-butyl 3-[4-[(E)-3-methoxy-3-oxoprop-1-enyl]-2-nitroanilino]piperidine-1-carboxylate
  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

文献信息

• Discovery of (2<i>E</i>)-3-{2-Butyl-1-[2-(diethylamino)ethyl]-1<i>H</i>-benzimidazol-5-yl}-<i>N</i>-hydroxyacrylamide (SB939), an Orally Active Histone Deacetylase Inhibitor with a Superior Preclinical Profile
  作者：Haishan Wang、Niefang Yu、Dizhong Chen、Ken Chi Lik Lee、Pek Ling Lye、Joyce Wei Wei Chang、Weiping Deng、Melvin Chi Yeh Ng、Ting Lu、Mui Ling Khoo、Anders Poulsen、Kanda Sangthongpitag、Xiaofeng Wu、Changyong Hu、Kee Chuan Goh、Xukun Wang、Lijuan Fang、Kay Lin Goh、Hwee Hoon Khng、Siok Kun Goh、Pauline Yeo、Xin Liu、Zahid Bonday、Jeanette M. Wood、Brian W. Dymock、Ethirajulu Kantharaj、Eric T. Sun

  DOI：10.1021/jm2003552

  日期：2011.7.14

  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.