4-(2-(4-((6-aminopyridin-3-yl)sulfonyl)piperazin-1-yl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)but-3-yn-1-ol | 1620098-74-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-(2-(4-((6-aminopyridin-3-yl)sulfonyl)piperazin-1-yl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)but-3-yn-1-ol
• 英文别名: 4-[2-[4-(6-Aminopyridin-3-yl)sulfonylpiperazin-1-yl]-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]but-3-yn-1-ol；4-[2-[4-(6-aminopyridin-3-yl)sulfonylpiperazin-1-yl]-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl]but-3-yn-1-ol
• CAS: 1620098-74-9
• 化学式: C₂₁H₂₁F₆N₅O₄S
• 分子量: 553.485
• InChiKey: AAYMCJNHVXSVMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  141
• 氢给体数：
  3
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  tert-butyl 4-(3-bromo-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)piperazine-1-carboxylate 在 copper(l) iodide 、 四(三苯基膦)钯 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 4-(2-(4-((6-aminopyridin-3-yl)sulfonyl)piperazin-1-yl)-5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-3-yl)but-3-yn-1-ol
  参考文献：
  名称：

  Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket

  摘要：

  Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the Xray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound Si was potent in both biochemical and cellular assays (IC50 = 0.005 mu M and EC50 = 0.205 mu M, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.

  DOI：

  10.1021/jm5001979

文献信息

• Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket
  作者：Fang-Tsao Hong、Mark H. Norman、Kate S. Ashton、Michael D. Bartberger、Jie Chen、Samer Chmait、Rod Cupples、Christopher Fotsch、Steven R. Jordan、David J. Lloyd、Glenn Sivits、Seifu Tadesse、Clarence Hale、David J. St. Jean

  DOI：10.1021/jm5001979

  日期：2014.7.24

  Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the Xray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound Si was potent in both biochemical and cellular assays (IC50 = 0.005 mu M and EC50 = 0.205 mu M, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.