(S)-2-(5-chloro-6-(2-(prop-1-yn-1-yl)piperazin-1-yl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol | 1450621-84-7

• 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: (S)-2-(5-chloro-6-(2-(prop-1-yn-1-yl)piperazin-1-yl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol
• 英文别名: 2-(5-chloro-6-((2S)-2-(1-propyn-1-yl)-1-piperazinyl)-3-pyridinyl)-1,1,1,3,3,3-hexafluoro-2-propanol；2-[5-chloro-6-[(2S)-2-prop-1-ynylpiperazin-1-yl]pyridin-3-yl]-1,1,1,3,3,3-hexafluoropropan-2-ol
• CAS: 1450621-84-7
• 化学式: C₁₅H₁₄ClF₆N₃O
• 分子量: 401.739
• InChiKey: QQXQOLLOHPEZOQ-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  48.4
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (S)-2-(5-chloro-6-(2-(prop-1-yn-1-yl)piperazin-1-yl)pyridin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 在 盐酸 、 caesium carbonate 、 三乙胺 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 2.17h， 生成 (S)-2-(6-(4-((6-aminopyridin-3-yl)sulfonyl)-2-(prop-1-yn-1-yl)-piperazin-1-yl)-5-(prop-1-yn-1-yl)pyridin-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
• 作为产物：
  描述：

  5,6-二氯烟酸 在 草酰氯 、 1-氯乙基氯甲酸酯 、 氯(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2-氨基乙基苯基)]钯(II) 、 四甲基氟化铵 、 potassium carbonate 、 sodium t-butanolate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (S)-2-(5-chloro-6-(2-(prop-1-yn-1-yl)piperazin-1-yl)pyridin-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

• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• 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.