2-benzyloxycarbonylamino-N-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]phenyl}acetoamide | 1422008-55-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-benzyloxycarbonylamino-N-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]phenyl}acetoamide
• CAS: 1422008-55-6
• 化学式: C₂₉H₃₆N₄O₉
• 分子量: 584.626
• InChiKey: MHPSPSYTMDABQC-DEPSJERBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.17
• 重原子数：
  42.0
• 可旋转键数：
  11.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  195.49
• 氢给体数：
  7.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  2-benzyloxycarbonylamino-N-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]phenyl}acetoamide 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 水 为溶剂， 反应 1.0h， 以85%的产率得到2-amino-N-[4-[[5-propan-2-yl-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1H-pyrazol-4-yl]methyl]phenyl]acetamide
  参考文献：
  名称：

  Design, synthesis, and structure–activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1)

  摘要：

  Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl beta-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an alpha-glucosidase inhibitor (alpha-GI) widely used in the clinic. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.041
• 作为产物：
  描述：

  异丁酰醋酸甲酯 在 哌啶 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 苄基三丁基氯化铵 、 1-羟基苯并三唑 、 一水合肼 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 甲苯 为溶剂， 反应 7.0h， 生成 2-benzyloxycarbonylamino-N-{4-[3-(β-d-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]phenyl}acetoamide
  参考文献：
  名称：

  Design, synthesis, and structure–activity relationships of a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-d-glycopyranosides substituted with novel hydrophilic groups as highly potent inhibitors of sodium glucose co-transporter 1 (SGLT1)

  摘要：

  Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl beta-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an alpha-glucosidase inhibitor (alpha-GI) widely used in the clinic. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.041