3-amino-N-[4-[(3-oxo-5-propan-2-yl-1,2-dihydropyrazol-4-yl)methyl]phenyl]propanamide | 1422008-80-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 3-amino-N-[4-[(3-oxo-5-propan-2-yl-1,2-dihydropyrazol-4-yl)methyl]phenyl]propanamide
• CAS: 1422008-80-7
• 化学式: C₁₆H₂₂N₄O₂
• 分子量: 302.376
• InChiKey: VYFZVVCMJKSVBZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  96.2
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(benzyloxycarbonylamino)propionylamino]phenyl}methyl)-5-isopropyl-1H-pyrazole 在 palladium 10% on activated carbon 、 β-glucuronidase 、 氢气 、 sodium methylate 作用下， 以 甲醇 、 水 为溶剂， 反应 2.0h， 生成 3-amino-N-[4-[(3-oxo-5-propan-2-yl-1,2-dihydropyrazol-4-yl)methyl]phenyl]propanamide
  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

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.