3-(N-methyl-anilino)-5-benzylthio-1,2,4-triazole

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 3-(N-methyl-anilino)-5-benzylthio-1,2,4-triazole
• 英文别名: 3-(benzylsulfanyl)-N-methyl-N-phenyl-1H-1,2,4-triazol-5-amine；3-benzylsulfanyl-N-methyl-N-phenyl-1H-1,2,4-triazol-5-amine
• 化学式: C₁₆H₁₆N₄S
• 分子量: 296.396
• InChiKey: DCEFGRIIZPWPQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-anilino-5-mercapto-1,2,4-triazole 在 sodium hydride 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-(N-methyl-anilino)-5-benzylthio-1,2,4-triazole
  参考文献：
  名称：

  Highly Potent Inhibitors of Methionine Aminopeptidase-2 Based on a 1,2,4-Triazole Pharmacophore

  摘要：

  High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.

  DOI：

  10.1021/jm061182w

文献信息

• Highly Potent Inhibitors of Methionine Aminopeptidase-2 Based on a 1,2,4-Triazole Pharmacophore
  作者：Joseph P. Marino,、Paul W. Fisher、Glenn A. Hofmann、Robert B. Kirkpatrick、Cheryl A. Janson、Randall K. Johnson、Chun Ma、Michael Mattern、Thomas D. Meek、M. Dominic Ryan、Christina Schulz、Ward W. Smith、David G. Tew、Thaddeus A. Tomazek、Daniel F. Veber、Wenfang C. Xiong、Yuuichi Yamamoto、Keizo Yamashita、Guang Yang、Scott K. Thompson

  DOI：10.1021/jm061182w

  日期：2007.8.1

  High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.