2-(6-chloro-5-methoxypyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol | 1620098-57-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(6-chloro-5-methoxypyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol
• CAS: 1620098-57-8
• 化学式: C₉H₆ClF₆NO₂
• 分子量: 309.596
• InChiKey: RSSCORHRBNPJQU-UHFFFAOYSA-N

物化性质

• 沸点：
  316.1±42.0 °C(Predicted)
• 密度：
  1.555±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  42.4
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-(6-chloro-5-methoxypyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 在 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 2.5h， 生成
  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
• 作为产物：
  描述：

  6-氯-5-甲氧基烟酸 在 草酰氯 、 四甲基氟化铵 作用下， 以 乙二醇二甲醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 2-(6-chloro-5-methoxypyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-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: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis
  作者：Nuria A. Tamayo、Mark H. Norman、Michael D. Bartberger、Fang-Tsao Hong、Yunxin Bo、Longbin Liu、Nobuko Nishimura、Kevin C. Yang、Seifu Tadesse、Christopher Fotsch、Jie Chen、Samer Chmait、Rod Cupples、Clarence Hale、Steven R. Jordan、David J. Lloyd、Glenn Sivits、Gwyneth Van、David J. St. Jean

  DOI：10.1021/jm5018175

  日期：2015.6.11

  a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure–activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to

  葡萄糖激酶-葡萄糖激酶调节蛋白（GK-GKRP）复合物在控制肝脏中葡萄糖稳态方面起着重要作用。我们最近公开了一系列芳基哌嗪作为GK-GKRP复合物的体外和体内破坏剂，在2型糖尿病（T2DM）啮齿动物模型中具有功效。在这里，我们描述了一类新的芳基砜作为GK-GKRP配合物的破坏剂，其中中央哌嗪支架已被一个芳香族基团取代。构象分析和这种新型化合物的结构-活性关系的探索导致了有效的GK-GKRP干扰物的鉴定。该新型系列的进一步优化可提供噻唑砜93能够在体外和体内破坏GK-GKRP相互作用，从而增加未结合GK的细胞质水平。