N-((R)-1-benzothiophen-2-yl(2-chlorophenyl)methyl)-2,3-dihydro-1,4-benzodioxine-6-sulfonamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并二恶烷
• 英文名称: N-((R)-1-benzothiophen-2-yl(2-chlorophenyl)methyl)-2,3-dihydro-1,4-benzodioxine-6-sulfonamide
• 英文别名: N-[(R)-1-benzothiophen-2-yl-(2-chlorophenyl)methyl]-2,3-dihydro-1,4-benzodioxine-6-sulfonamide
• 化学式: C₂₃H₁₈ClNO₄S₂
• 分子量: 471.985
• InChiKey: LBZRWOSPKDKIOG-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,3-二氢-1,4-苯并二氧-6-磺酰氯 、 (R)-1-(1-benzothiophen-2-yl)-1-(2-chlorophenyl)methanamine 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 47.0h， 以33%的产率得到N-((R)-1-benzothiophen-2-yl(2-chlorophenyl)methyl)-2,3-dihydro-1,4-benzodioxine-6-sulfonamide
  参考文献：
  名称：

  Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n_N → σ*_S–X) Interaction for Conformational Constraint

  摘要：

  The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 mu M) was optimized to lead compound 32 (AMG-0696; hcK hGKRP IC50 = 0.0038 mu M). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n(N) -> sigma*(S-X)) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GI( translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.

  DOI：

  10.1021/acs.jmedchem.5b01367

文献信息

• Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n_N → σ*_S–X) Interaction for Conformational Constraint
  作者：Lewis D. Pennington、Michael D. Bartberger、Michael D. Croghan、Kristin L. Andrews、Kate S. Ashton、Matthew P. Bourbeau、Jie Chen、Samer Chmait、Rod Cupples、Christopher Fotsch、Joan Helmering、Fang-Tsao Hong、Randall W. Hungate、Steven R. Jordan、Ke Kong、Longbin Liu、Klaus Michelsen、Carolyn Moyer、Nobuko Nishimura、Mark H. Norman、Andreas Reichelt、Aaron C. Siegmund、Glenn Sivits、Seifu Tadesse、Christopher M. Tegley、Gwyneth Van、Kevin C. Yang、Guomin Yao、Jiandong Zhang、David J. Lloyd、Clarence Hale、David J. St. Jean

  DOI：10.1021/acs.jmedchem.5b01367

  日期：2015.12.24

  The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 mu M) was optimized to lead compound 32 (AMG-0696; hcK hGKRP IC50 = 0.0038 mu M). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n(N) -> sigma*(S-X)) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GI( translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.