2-(butylmethylamino)-5-nitronicotinic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 2-(butylmethylamino)-5-nitronicotinic acid
• 英文别名: 2-[Butyl(methyl)amino]-5-nitropyridine-3-carboxylic acid；2-[butyl(methyl)amino]-5-nitropyridine-3-carboxylic acid
• 化学式: C₁₁H₁₅N₃O₄
• 分子量: 253.258
• InChiKey: HGHCTWKWGDEHLY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  99.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(butylmethylamino)-5-nitronicotinic acid 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 12.0h， 生成 5-amino-2-(butylmethylamino)nicotinic acid
  参考文献：
  名称：

  Computer-aided discovery of aminopyridines as novel JAK2 inhibitors

  摘要：

  The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancers. For this reason, we sought to identify novel small molecule inhibitors of JAK2. Using Surflex-Dock software, we tested 3010 compounds with known chemical structures in silico for their ability to interact with the JAK2 ATP-binding pocket. We selected the 10 highest-scoring compounds and tested their abilities to inhibit JAK2 activity in vitro. Compound 1a (ethyl 1-(5-((3-methoxyphenyl)carbamoyl)-3-nitropyridin-2-yl)piperidine-4-carboxylate) was identified. Optimization of 1a using docking studies led to the discovery of compounds 1b and 1d, potent JAK2 inhibitors. Furthermore, as V-shaped kinase inhibitors can curve around the protein backbone and access deep into the pocket, we developed a new series of compounds with a non-linear sulfonamide bond. Nine compounds were prepared and evaluated for JAK2 inhibitory effects. Compounds 7e (IC50 = 6.9 mu M) and 7h (IC50 = 12.2 mu M) showed better JAK2 inhibition, validating our design approach. This study successfully applied virtual screening for hit discovery, and a docking study for hit optimization. In addition, a novel approach to drug discovery, combining structure-and shape-based drug design, facilitated the design of more potent JAK2 inhibitors. The methods provide a guide for future development of inhibitors targeting JAK2 and other kinases. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.016
• 作为产物：
  描述：

  2-氯-3-甲基-5-硝基吡啶 在 sodium dichromate 、 硫酸 作用下， 以 乙酸乙酯 为溶剂， 反应 1.0h， 生成 2-(butylmethylamino)-5-nitronicotinic acid
  参考文献：
  名称：

  Computer-aided discovery of aminopyridines as novel JAK2 inhibitors

  摘要：

  The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancers. For this reason, we sought to identify novel small molecule inhibitors of JAK2. Using Surflex-Dock software, we tested 3010 compounds with known chemical structures in silico for their ability to interact with the JAK2 ATP-binding pocket. We selected the 10 highest-scoring compounds and tested their abilities to inhibit JAK2 activity in vitro. Compound 1a (ethyl 1-(5-((3-methoxyphenyl)carbamoyl)-3-nitropyridin-2-yl)piperidine-4-carboxylate) was identified. Optimization of 1a using docking studies led to the discovery of compounds 1b and 1d, potent JAK2 inhibitors. Furthermore, as V-shaped kinase inhibitors can curve around the protein backbone and access deep into the pocket, we developed a new series of compounds with a non-linear sulfonamide bond. Nine compounds were prepared and evaluated for JAK2 inhibitory effects. Compounds 7e (IC50 = 6.9 mu M) and 7h (IC50 = 12.2 mu M) showed better JAK2 inhibition, validating our design approach. This study successfully applied virtual screening for hit discovery, and a docking study for hit optimization. In addition, a novel approach to drug discovery, combining structure-and shape-based drug design, facilitated the design of more potent JAK2 inhibitors. The methods provide a guide for future development of inhibitors targeting JAK2 and other kinases. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.016

文献信息

• Computer-aided discovery of aminopyridines as novel JAK2 inhibitors
  作者：Chao Zhao、Su Hui Yang、Daulat Bikram Khadka、Yifeng Jin、Kyung-Tae Lee、Won-Jea Cho

  DOI：10.1016/j.bmc.2015.01.016

  日期：2015.3

  The Janus kinase 2 (JAK2)-mediated signaling pathway plays an important role in controlling cell survival, proliferation, and differentiation. In recent years, genetic, biological, and physiological evidence has established JAK2 inhibitors as effective chemotherapeutic agents for the treatment of many different cancers. For this reason, we sought to identify novel small molecule inhibitors of JAK2. Using Surflex-Dock software, we tested 3010 compounds with known chemical structures in silico for their ability to interact with the JAK2 ATP-binding pocket. We selected the 10 highest-scoring compounds and tested their abilities to inhibit JAK2 activity in vitro. Compound 1a (ethyl 1-(5-((3-methoxyphenyl)carbamoyl)-3-nitropyridin-2-yl)piperidine-4-carboxylate) was identified. Optimization of 1a using docking studies led to the discovery of compounds 1b and 1d, potent JAK2 inhibitors. Furthermore, as V-shaped kinase inhibitors can curve around the protein backbone and access deep into the pocket, we developed a new series of compounds with a non-linear sulfonamide bond. Nine compounds were prepared and evaluated for JAK2 inhibitory effects. Compounds 7e (IC50 = 6.9 mu M) and 7h (IC50 = 12.2 mu M) showed better JAK2 inhibition, validating our design approach. This study successfully applied virtual screening for hit discovery, and a docking study for hit optimization. In addition, a novel approach to drug discovery, combining structure-and shape-based drug design, facilitated the design of more potent JAK2 inhibitors. The methods provide a guide for future development of inhibitors targeting JAK2 and other kinases. (C) 2015 Elsevier Ltd. All rights reserved.