diethyl {2-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl}malonate | 1359669-62-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: diethyl {2-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl}malonate
• CAS: 1359669-62-7
• 化学式: C₃₀H₃₃NO₅
• 分子量: 487.596
• InChiKey: HSILZQDSEBAOCK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.72
• 重原子数：
  36.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  74.72
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  diethyl {2-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl}malonate 在 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 甲苯 为溶剂， 反应 14.5h， 以38%的产率得到{2-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl}acetic acid
  参考文献：
  名称：

  Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

  摘要：

  The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.

  DOI：

  10.1021/jm2012968
• 作为产物：
  描述：

  2-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol 在 吡啶 、 氯化亚砜 、 sodium hydride 作用下， 以 四氢呋喃 、 甲苯 、 mineral oil 为溶剂， 反应 16.0h， 生成 diethyl {2-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl}malonate
  参考文献：
  名称：

  Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

  摘要：

  The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to beta-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.

  DOI：

  10.1021/jm2012968