4-(2,4-dichlorobenzyloxy)-2-methylaniline

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 4-(2,4-dichlorobenzyloxy)-2-methylaniline
• 英文别名: 4-[(2,4-Dichlorophenyl)methoxy]-2-methylaniline
• 化学式: C₁₄H₁₃Cl₂NO
• mdl: MFCD11116577
• 分子量: 282.169
• InChiKey: YTHPXUKPRFLCNK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.142
• 拓扑面积：
  35.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(2,4-dichlorobenzyloxy)-2-methylaniline 、 (Z)-ethyl 6-(tosyloxy)hex-2-enoate 在 碳酸氢钠 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 5.0h， 生成 (S)-2-(1-(4-(2,4-dichlorobenzyloxy)-2-methylphenyl)pyrrolidin-2-yl)acetic acid hydrochloride
  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：

  4-硝基间甲苯酚 在 potassium carbonate 、 锌 作用下， 以 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 4-(2,4-dichlorobenzyloxy)-2-methylaniline
  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

• Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
  作者：Elizabeth A. Jurica、Ximao Wu、Kristin N. Williams、Andres S. Hernandez、David S. Nirschl、Richard A. Rampulla、Arvind Mathur、Min Zhou、Gary Cao、Chunshan Xie、Biji Jacob、Hong Cai、Tao Wang、Brian J. Murphy、Heng Liu、Carrie Xu、Lori K. Kunselman、Michael B. Hicks、Qin Sun、Dora M. Schnur、Doree F. Sitkoff、Elizabeth A. Dierks、Atsu Apedo、Douglas B. Moore、Kimberly A. Foster、Mary Ellen Cvijic、Reshma Panemangalore、Neil A. Flynn、Brad D. Maxwell、Yang Hong、Yuan Tian、Jason J. Wilkes、Bradley A. Zinker、Jean M. Whaley、Joel C. Barrish、Jeffrey A. Robl、William R. Ewing、Bruce A. Ellsworth

  DOI：10.1021/acs.jmedchem.6b01559

  日期：2017.2.23

  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.