methyl 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetate | 1610033-10-7

• 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: methyl 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetate
• 英文别名: methyl 2-[(2R,4R)-1-[4-[1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl]oxyphenyl]-4-(trifluoromethyl)pyrrolidin-2-yl]acetate
• CAS: 1610033-10-7
• 化学式: C₂₆H₃₀F₄N₂O₄
• 分子量: 510.529
• InChiKey: KRGQTRKJDPGPCV-IEBWSBKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  51.2
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  methyl 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetate 在 水 、 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以42%的产率得到2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-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 、 二氯甲烷 、 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 26.92h， 生成 methyl 2-((2R,4R)-1-(4-((1-(2-fluoro-5-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetate
  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。
• Optimization of physicochemical properties of pyrrolidine GPR40 AgoPAMs results in a differentiated profile with improved pharmacokinetics and reduced off-target activities
  作者：Elizabeth A. Jurica、Ximao Wu、Kristin N. Williams、Lauren E. Haque、Richard A. Rampulla、Arvind Mathur、Min Zhou、Gary Cao、Hong Cai、Tao Wang、Heng Liu、Carrie Xu、Lori K. Kunselman、Thomas M. Antrilli、Michael B. Hicks、Qin Sun、Elizabeth A. Dierks、Atsu Apedo、Douglas B. Moore、Kimberly A. Foster、Mary Ellen Cvijic、Reshma Panemangalore、Purnima Khandelwal、Jason J. Wilkes、Bradley A. Zinker、Donald G. Robertson、Evan B. Janovitz、Michael Galella、Yi-Xin Li、Julia Li、Thangeswaran Ramar、Prasada Rao Jalagam、Ramya Jayaram、Jean M. Whaley、Joel C. Barrish、Jeffrey A. Robl、William R. Ewing、Bruce A. Ellsworth

  DOI：10.1016/j.bmc.2023.117273

  日期：2023.5