2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile | 1610033-40-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile
• 英文别名: 2-[(2R,4R)-1-[4-[1-(2-fluoro-5-methoxyphenyl)pyrrolidin-3-yl]oxyphenyl]-4-(trifluoromethyl)pyrrolidin-2-yl]acetonitrile
• CAS: 1610033-40-3
• 化学式: C₂₄H₂₅F₄N₃O₂
• 分子量: 463.475
• InChiKey: QGVBYJNZOSOXPY-JUAJCIKASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  48.7
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile 在 水 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 1.5h， 生成 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid
  参考文献：
  名称：

  Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

  摘要：

  G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote,glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly I selectiveand potent GPR40 agonists with a dual mechanism of action, promoting both ghicose-clependent insulin and incretin secretion. Employing strategies to increase fiolarity and the ratio of sp(3)/sP(2) character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

  DOI：

  10.1021/acs.jmedchem.7b00982
• 作为产物：
  描述：

  顺式-4-羟基-D-脯氨酸盐酸盐 在 N-甲基吗啉 、 吡啶 、 chromium(VI) oxide 、 盐酸 、 sodium tetrahydroborate 、 copper(l) iodide 、 氯化亚砜 、 硫酸 、 palladium 10% on activated carbon 、 四丁基氟化铵 、 氢气 、 caesium carbonate 、 溶剂黄146 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 、 正丁醇 为溶剂， -10.0~110.0 ℃ 、101.33 kPa 条件下， 反应 41.92h， 生成 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile
  参考文献：
  名称：

  Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

  摘要：

  G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote,glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly I selectiveand potent GPR40 agonists with a dual mechanism of action, promoting both ghicose-clependent insulin and incretin secretion. Employing strategies to increase fiolarity and the ratio of sp(3)/sP(2) character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

  DOI：

  10.1021/acs.jmedchem.7b00982

文献信息

• [EN] PYRROLIDINE GPR40 MODULATORS<br/>[FR] MODULATEURS PYRROLIDINES DE GPR40
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2014078609A1

  公开（公告）日：2014-05-22

  The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.

  本发明提供了式(I)的化合物：或其立体异构体，或其药物可接受的盐，其中所有变量均如本文所述定义。这些化合物是GPR40 G蛋白偶联受体的调节剂，可用作药物。
• PYRROLIDINE GPR40 MODULATORS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20160280680A1

  公开（公告）日：2016-09-29

  The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.
• US9714231B2
  申请人：——

  公开号：US9714231B2

  公开（公告）日：2017-07-25