N-(((R)-2-chlorophenyl)([1,3]thiazolo[5,4-b]pyridin-2-yl)methyl)-3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonamide | 1402598-57-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(((R)-2-chlorophenyl)([1,3]thiazolo[5,4-b]pyridin-2-yl)methyl)-3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonamide
• 英文别名: N-[(R)-(2-chlorophenyl)-([1,3]thiazolo[5,4-b]pyridin-2-yl)methyl]-3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonamide
• CAS: 1402598-57-5
• 化学式: C₂₂H₁₈ClN₃O₄S₂
• 分子量: 487.988
• InChiKey: ICOXSWPOKXQVLK-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  127
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonamide 在 正丁基锂 作用下， 以 四氢呋喃 、 二氧化碳 、 异丙醇 、 甲苯 为溶剂， 反应 19.34h， 生成 N-(((R)-2-chlorophenyl)([1,3]thiazolo[5,4-b]pyridin-2-yl)methyl)-3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonamide 、 N-((S)-(2-chlorophenyl)([1,3]thiazolo[5,4-b]pyridin-2-yl)methyl)-3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonamide
  参考文献：
  名称：

  [EN] BENZODIOXEPINE AND BENZODIOXINE COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES
  [FR] BENZODIOXÉPINE ET COMPOSÉS DE BENZODIOXINE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE POUR LE TRAITEMENT DU DIABÈTE

  摘要：

  本发明涉及与葡萄糖激酶调节蛋白相互作用的式I或II的化合物，或其药学上可接受的盐。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。

  公开号：

  WO2012138776A1

文献信息

• [EN] BENZODIOXEPINE AND BENZODIOXINE COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES<br/>[FR] BENZODIOXÉPINE ET COMPOSÉS DE BENZODIOXINE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE POUR LE TRAITEMENT DU DIABÈTE
  申请人：AMGEN INC

  公开号：WO2012138776A1

  公开（公告）日：2012-10-11

  The present invention relates to compounds of formula I or II, or pharmaceutically acceptable salts thereof, 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式I或II的化合物，或其药学上可接受的盐。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。
• BENZODIOXEPINE AND BENZODIOXINE COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES
  申请人：Bartberger Michael David

  公开号：US20140155415A1

  公开（公告）日：2014-06-05

  The present invention relates to compounds of formula I or II, or pharmaceutically acceptable salts thereof, 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.

  本发明涉及公式I或II的化合物，或其药学上可接受的盐，其与葡萄糖激酶调节蛋白相互作用。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/或状况的方法，以及含有这些化合物或其药学上可接受的盐的制药组合物。
• 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.