3-cyclopropyl-3-(3-((1-(2-(3,3-dimethylbutyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propanoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3-cyclopropyl-3-(3-((1-(2-(3,3-dimethylbutyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propanoic acid
• 英文别名: 3-Cyclopropyl-3-[3-[[1-[2-(3,3-dimethylbutyl)-5-methoxyphenyl]piperidin-4-yl]methoxy]phenyl]propanoic acid；3-cyclopropyl-3-[3-[[1-[2-(3,3-dimethylbutyl)-5-methoxyphenyl]piperidin-4-yl]methoxy]phenyl]propanoic acid
• 化学式: C₃₁H₄₃NO₄
• 分子量: 493.687
• InChiKey: AQPHVUYTWUOUSR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.6
• 重原子数：
  36
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-环丙基-3-(3-羟基苯基)丙酸 在 偶氮二甲酸二异丙酯 、 硫酸 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 23.0h， 生成 3-cyclopropyl-3-(3-((1-(2-(3,3-dimethylbutyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)propanoic acid
  参考文献：
  名称：

  Design and Identification of a GPR40 Full Agonist (SCO-267) Possessing a 2-Carbamoylphenyl Piperidine Moiety

  摘要：

  GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic beta-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular pi-pi stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.

  DOI：

  10.1021/acs.jmedchem.0c00843

文献信息

• AROMATIC COMPOUND
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US20200039957A1

  公开（公告）日：2020-02-06

  Provided is a novel aromatic ring compound which may have a GPR40 agonist activity and a GLP-1 secretagogue action. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof may have a GPR40 agonist activity and a GLP-1 secretagogue action, may be useful for the prophylaxis or treatment of cancer, obesity, diabetes, hypertension, hyperlipidemia, cardiac failure, diabetic complications, metabolic syndrome, sarcopenia and the like, and may afford superior efficacy.

  提供了一种新颖的芳香环化合物，可能具有GPR40激动剂活性和GLP-1分泌素作用。式（I）所代表的化合物：其中每个符号如描述中所述，或其盐可能具有GPR40激动剂活性和GLP-1分泌素作用，可能用于预防或治疗癌症、肥胖症、糖尿病、高血压、高脂血症、心力衰竭、糖尿病并发症、代谢综合征、肌少症等，并可能具有更优越的疗效。
• Aromatic compound
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US11186565B2

  公开（公告）日：2021-11-30

  Provided is a novel aromatic ring compound which may have a GPR40 agonist activity and a GLP-1 secretagogue action. A compound represented by the formula (I): wherein each symbol is as described in the DESCRIPTION, or a salt thereof may have a GPR40 agonist activity and a GLP-1 secretagogue action, may be useful for the prophylaxis or treatment of cancer, obesity, diabetes, hypertension, hyperlipidemia, cardiac failure, diabetic complications, metabolic syndrome, sarcopenia and the like, and may afford superior efficacy.

  本研究提供了一种新型芳香环化合物，它可能具有 GPR40 激动剂活性和 GLP-1 促泌作用。由式（I）代表的化合物： 其中各符号如说明书所述，或其盐类可能具有 GPR40 激动剂活性和 GLP-1 促泌剂作用，可用于预防或治疗癌症、肥胖症、糖尿病、高血压、高脂血症、心力衰竭、糖尿病并发症、代谢综合征、肌肉疏松症等，并可能具有更优越的疗效。
• Design and Identification of a GPR40 Full Agonist (<b>SCO-267</b>) Possessing a 2-Carbamoylphenyl Piperidine Moiety
  作者：Hideki Furukawa、Yasufumi Miyamoto、Yasuhiro Hirata、Koji Watanabe、Yuko Hitomi、Yayoi Yoshitomi、Jumpei Aida、Naoyoshi Noguchi、Nobuyuki Takakura、Kazuaki Takami、Seiji Miwatashi、Yoshihiko Hirozane、Teruki Hamada、Ryo Ito、Mitsugi Ookawara、Yusuke Moritoh、Masanori Watanabe、Tsuyoshi Maekawa

  DOI：10.1021/acs.jmedchem.0c00843

  日期：2020.9.24

  GPR40/FFAR1 is a G-protein-coupled receptor expressed in pancreatic beta-cells and enteroendocrine cells. GPR40 activation stimulates secretions of insulin and incretin, both of which are the pivotal regulators of glycemic control. Therefore, a GPR40 agonist is an attractive target for the treatment of type 2 diabetes mellitus. Using the reported biaryl derivative 1, we shifted the hydrophobic moiety to the terminal aryl ring and replaced the central aryl ring with piperidine, generating 2-(4,4-dimethylpentyl)phenyl piperidine 4a, which had improved potency for GPR40 and high lipophilicity. We replaced the hydrophobic moiety with N-alkyl-N-aryl benzamides to lower the lipophilicity and restrict the N-alkyl moieties to the presumed lipophilic pocket using the intramolecular pi-pi stacking of cis-preferential N-alkyl-N-aryl benzamide. Among these, orally available (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid (SCO-267) effectively stimulated insulin secretion and GLP-1 release and ameliorated glucose tolerance in diabetic rats via GPR40 full agonism.