[(3S)-6-({2',6'-dimethyl-4'-[(1-methylpiperidin-4-yl)oxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid | 1373551-58-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: [(3S)-6-({2',6'-dimethyl-4'-[(1-methylpiperidin-4-yl)oxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid
• 英文别名: 2-[(3S)-6-[[3-[2,6-dimethyl-4-(1-methylpiperidin-4-yl)oxyphenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid
• CAS: 1373551-58-6
• 化学式: C₃₁H₃₅NO₅
• 分子量: 501.623
• InChiKey: LQXKEVYUMXREMM-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  68.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  [(3S)-6-({2',6'-dimethyl-4'-[(1-methylpiperidin-4-yl)oxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 以91 mg的产率得到[(3S)-6-({2',6'-dimethyl-4'-[(1-methylpiperidin-4-yl)oxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hydrochloride
  参考文献：
  名称：

  Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent

  摘要：

  G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic beta-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 mu M (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to beta-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.

  DOI：

  10.1021/jm300170m
• 作为产物：
  描述：

  1-甲基-4-哌啶醇 在 水 、 三苯基膦 、 sodium hydroxide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 38.0h， 生成 [(3S)-6-({2',6'-dimethyl-4'-[(1-methylpiperidin-4-yl)oxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid
  参考文献：
  名称：

  Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent

  摘要：

  G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic beta-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 mu M (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to beta-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.

  DOI：

  10.1021/jm300170m

文献信息

• [EN] POLYCYCLIC DERIVATIVES, PREPARATION METHOD AND MEDICAL USES THEREOF<br/>[FR] DÉRIVÉS POLYCYCLIQUES, LEUR PROCÉDÉ DE PRÉPARATION ET LEURS UTILISATIONS MÉDICALES
  申请人：JIANGSU HENGRUI MEDICINE CO

  公开号：WO2013104257A1

  公开（公告）日：2013-07-18

  本发明公开了一种通式（I）所示的多环类衍生物、其制备方法及含有该衍生物的药物组合物，及其作为治疗剂，特别是GPR40激动剂和在制备治疗糖尿病和代谢性病症等疾病的药物中的用途，其中通式（I）的各取代基与说明书中的定义相同。
• Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent
  作者：Nobuyuki Negoro、Shinobu Sasaki、Satoshi Mikami、Masahiro Ito、Yoshiyuki Tsujihata、Ryo Ito、Masami Suzuki、Koji Takeuchi、Nobuhiro Suzuki、Junichi Miyazaki、Takashi Santou、Tomoyuki Odani、Naoyuki Kanzaki、Miyuki Funami、Akio Morohashi、Masami Nonaka、Shinichiro Matsunaga、Tsuneo Yasuma、Yu Momose

  DOI：10.1021/jm300170m

  日期：2012.4.26

  G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic beta-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 mu M (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to beta-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.