4-(4-hydroxy-2-methylphenylmethyl)-5-isopropyl-1H-pyrazol-3-yl β-d-glucopyranoside | 667937-69-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(4-hydroxy-2-methylphenylmethyl)-5-isopropyl-1H-pyrazol-3-yl β-d-glucopyranoside
• 英文别名: (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-[[4-[(4-hydroxy-2-methylphenyl)methyl]-5-propan-2-yl-1H-pyrazol-3-yl]oxy]oxane-3,4,5-triol
• CAS: 667937-69-1
• 化学式: C₂₀H₂₈N₂O₇
• 分子量: 408.452
• InChiKey: WVGZFGBLAOTZSN-NWDGLCLDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  148
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-(4-hydroxy-2-methylphenylmethyl)-5-isopropyl-1H-pyrazol-3-yl β-d-glucopyranoside 在 β-glucuronidase 作用下， 以 aq. acetate buffer 为溶剂， 以70%的产率得到4-[(4-Hydroxy-2-methylphenyl)methyl]-5-propan-2-yl-1,2-dihydropyrazol-3-one
  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：

  4-(4-benzyloxy-2-methylphenylmethyl)-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one 在 甲醇 、 palladium 10% on activated carbon 、 氢气 、 sodium methylate 、 苄基三丁基氯化铵 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 21.0h， 生成 4-(4-hydroxy-2-methylphenylmethyl)-5-isopropyl-1H-pyrazol-3-yl β-d-glucopyranoside
  参考文献：
  名称：

  Structure–activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia

  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 treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl beta-D-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats). (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.09.037

文献信息

• 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)
  作者：Nobuhiko Fushimi、Hirotaka Teranishi、Kazuo Shimizu、Shigeru Yonekubo、Kohsuke Ohno、Takashi Miyagi、Fumiaki Itoh、Toshihide Shibazaki、Masaki Tomae、Yukiko Ishikawa-Takemura、Takeshi Nakabayashi、Noboru Kamada、Yuji Yamauchi、Susumu Kobayashi、Masayuki Isaji

  DOI：10.1016/j.bmc.2012.11.041

  日期：2013.2

  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.
• Structure–activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia
  作者：Nobuhiko Fushimi、Hideki Fujikura、Hiroaki Shiohara、Hirotaka Teranishi、Kazuo Shimizu、Shigeru Yonekubo、Kohsuke Ohno、Takashi Miyagi、Fumiaki Itoh、Toshihide Shibazaki、Masaki Tomae、Yukiko Ishikawa-Takemura、Takeshi Nakabayashi、Noboru Kamada、Tomonaga Ozawa、Susumu Kobayashi、Masayuki Isaji

  DOI：10.1016/j.bmc.2012.09.037

  日期：2012.11

  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 treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl beta-D-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats). (C) 2012 Elsevier Ltd. All rights reserved.