2-((2S,4S)-1-(4-(2,6-dimethylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile | 1283146-34-8

• 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: 2-((2S,4S)-1-(4-(2,6-dimethylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile
• 英文别名: 2-[(2S,4S)-1-[4-(2,6-dimethylphenoxy)phenyl]-4-(trifluoromethyl)pyrrolidin-2-yl]acetonitrile
• CAS: 1283146-34-8
• 化学式: C₂₁H₂₁F₃N₂O
• 分子量: 374.406
• InChiKey: WRNRPZHWCDZFCX-FUHWJXTLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  36.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-((2S,4S)-1-(4-(2,6-dimethylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile 、 三氟乙酸 在 potassium hydroxide 作用下， 以 乙醇 、 水 、 乙腈 为溶剂， 反应 2.0h， 以92%的产率得到2-((2S,4S)-1-(4-(2,6-dimethylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid trifluoroacetic acid salt
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

  DOI：

  10.1021/acs.jmedchem.6b01559
• 作为产物：
  描述：

  (2S,4S)-N-叔丁氧基羰基-4-三氟甲基脯氨酸 在 N-甲基吗啉 、 吡啶 、 盐酸 、 sodium tetrahydroborate 、 copper(l) iodide 、 palladium 10% on activated carbon 、 氢气 、 copper diacetate 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 溶剂黄146 、 二甲基亚砜 、 乙酸乙酯 、 异丙醇 为溶剂， -10.0~90.0 ℃ 、101.33 kPa 条件下， 反应 5.75h， 生成 2-((2S,4S)-1-(4-(2,6-dimethylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile
  参考文献：
  名称：

  Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode

  摘要：

  A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding K-i and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both G(q)-coupled intracellular Ca2+ flux and G(s)-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.

  DOI：

  10.1021/acs.jmedchem.6b01559

文献信息

• PYRROLIDINE GPR40 MODULATORS
  申请人：Ellsworth Bruce A.

  公开号：US20110082165A1

  公开（公告）日：2011-04-07

  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，或药用可接受的盐，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。
• US8288404B2
  申请人：——

  公开号：US8288404B2

  公开（公告）日：2012-10-16
• [EN] PYRROLIDINE GPR40 MODULATORS<br/>[FR] MODULATEURS DU GPR40 À BASE DE PYRROLIDINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2011044073A1

  公开（公告）日：2011-04-14

  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.