2-((2S,4S)-1-(4-(4-(benzyloxy)-2-methylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid trifluoroacetic acid salt | 1283142-75-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-((2S,4S)-1-(4-(4-(benzyloxy)-2-methylphenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid trifluoroacetic acid salt
• CAS: 1283142-75-5
• 化学式: C₂HF₃O₂*C₂₇H₂₆F₃NO₄
• 分子量: 599.527
• InChiKey: XJUGBBRQFVTFQO-DTRWSJPISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.23
• 重原子数：
  42.0
• 可旋转键数：
  8.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  96.3
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  2-((2S,4S)-1-(4-hydroxyphenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile 在 吡啶 、 copper diacetate 、 potassium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 5.0h， 生成 2-((2S,4S)-1-(4-(4-(benzyloxy)-2-methylphenoxy)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