6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid | 1359669-08-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
• 英文别名: 6-[[3-[4-(2-Ethoxyethoxy)-2,6-dimethylphenyl]phenyl]methoxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
• CAS: 1359669-08-1
• 化学式: C₃₀H₃₄O₅
• 分子量: 474.597
• InChiKey: JQKZHQURTKMBJT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  65
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4'-羟基-2',6'-二甲基联苯-3-甲醛 在 sodium tetrahydroborate 、 三丁基膦 、 potassium carbonate 、 potassium iodide 、 sodium hydroxide 、 1,1'-azodicarbonyl-dipiperidine 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 20.0h， 生成 6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-1,2,3,4-tetrahydronaphthalene-2-carboxylic 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

文献信息

• Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists
  作者：Nobuyuki Negoro、Shinobu Sasaki、Masahiro Ito、Shuji Kitamura、Yoshiyuki Tsujihata、Ryo Ito、Masami Suzuki、Koji Takeuchi、Nobuhiro Suzuki、Junichi Miyazaki、Takashi Santou、Tomoyuki Odani、Naoyuki Kanzaki、Miyuki Funami、Toshimasa Tanaka、Tsuneo Yasuma、Yu Momose

  DOI：10.1021/jm2012968

  日期：2012.2.23

  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.