5-(Tert-butyl)isoxazole-3-carbohydrazide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5-(Tert-butyl)isoxazole-3-carbohydrazide
• 英文别名: 5-tert-butyl-1,2-oxazole-3-carbohydrazide
• 化学式: C₈H₁₃N₃O₂
• 分子量: 183.21
• InChiKey: FLZYTJCMZUHHGM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  81.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(Tert-butyl)isoxazole-3-carbohydrazide 在 碘 、 potassium carbonate 作用下， 以 二甲基亚砜 为溶剂， 反应 3.0h， 生成 2-(5-(tert-butyl)isoxazol-3-yl)-5-(3-chloro-5-fluorophenyl)-1,3,4-oxadiazole
  参考文献：
  名称：

  Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation

  摘要：

  A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H2O molecule. Both compounds 28 and 35 exhibited submicromolar potency of inhibiting the TLR3-dependent innate immune gene program, including ISG54, 1SG56, IL-8, and Gro beta genes in cultured human small airway epithelial cells (hSAEC5). More importantly, they also demonstrated potent efficacy reducing airway inflammation in a mouse model with low toxicity, indicating a proof of concept that BRD4 inhibitors may offer the therapeutic potential to block the viral induced airway inflammation. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.04.006
• 作为产物：
  描述：

  5-叔丁基基-异噁唑-3-甲酸乙酯 在 肼 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 5-(Tert-butyl)isoxazole-3-carbohydrazide
  参考文献：
  名称：

  Structure–Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N′-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists

  摘要：

  Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR ring as well as the 5-position of the results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl isoxazole moiety may allow for the development of more potent EPAC antagonists.

  DOI：

  10.1021/acs.jmedchem.5b00635

文献信息

• Structure–Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-<i>N</i>′-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists
  作者：Na Ye、Yingmin Zhu、Haijun Chen、Zhiqing Liu、Fang C. Mei、Christopher Wild、Haiying Chen、Xiaodong Cheng、Jia Zhou

  DOI：10.1021/acs.jmedchem.5b00635

  日期：2015.8.13

  Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR ring as well as the 5-position of the results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl isoxazole moiety may allow for the development of more potent EPAC antagonists.
• Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation
  作者：Zhiqing Liu、Bing Tian、Haiying Chen、Pingyuan Wang、Allan R. Brasier、Jia Zhou

  DOI：10.1016/j.ejmech.2018.04.006

  日期：2018.5

  A series of diverse small molecules have been designed and synthesized through structure-based drug design by taking advantage of fragment merging and elaboration approaches. Compounds ZL0420 (28) and ZL0454 (35) were identified as potent and selective BRD4 inhibitors with nanomolar binding affinities to bromodomains (BDs) of BRD4. Both of them can be well docked into the acetyl-lysine (KAc) binding pocket of BRD4, forming key interactions including the critical hydrogen bonds with Asn140 directly and Tyr97 indirectly via a H2O molecule. Both compounds 28 and 35 exhibited submicromolar potency of inhibiting the TLR3-dependent innate immune gene program, including ISG54, 1SG56, IL-8, and Gro beta genes in cultured human small airway epithelial cells (hSAEC5). More importantly, they also demonstrated potent efficacy reducing airway inflammation in a mouse model with low toxicity, indicating a proof of concept that BRD4 inhibitors may offer the therapeutic potential to block the viral induced airway inflammation. (C) 2018 Elsevier Masson SAS. All rights reserved.