(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl (2S)-(4-isopropylphenyl)[(2-methyl-3-oxo-5,7-dipropyl-2,3-dihydro-1,2-benzisoxazol-6-yl)oxy]acetate | 860780-53-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: (1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl (2S)-(4-isopropylphenyl)[(2-methyl-3-oxo-5,7-dipropyl-2,3-dihydro-1,2-benzisoxazol-6-yl)oxy]acetate
• 英文别名: [(2R)-1-oxo-1-pyrrolidin-1-ylpropan-2-yl] (2S)-2-[(2-methyl-3-oxo-5,7-dipropyl-1,2-benzoxazol-6-yl)oxy]-2-(4-propan-2-ylphenyl)acetate
• CAS: 860780-53-6
• 化学式: C₃₂H₄₂N₂O₆
• 分子量: 550.695
• InChiKey: XQDBNJKBIMHSKT-PIKZIKFNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  40
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  85.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl (2S)-(4-isopropylphenyl)[(2-methyl-3-oxo-5,7-dipropyl-2,3-dihydro-1,2-benzisoxazol-6-yl)oxy]acetate 在 lithium hydroxide 、 双氧水 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以93%的产率得到(S)-(4-Isopropyl-phenyl)-(2-methyl-3-oxo-5,7-dipropyl-2,3-dihydro-benzo[d]isoxazol-6-yloxy)-acetic acid
  参考文献：
  名称：

  Design and Synthesis of α-Aryloxyphenylacetic Acid Derivatives:  A Novel Class of PPARα/γ Dual Agonists with Potent Antihyperglycemic and Lipid Modulating Activity

  摘要：

  The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.

  DOI：

  10.1021/jm0502135
• 作为产物：
  描述：

  methyl 2,4-bis(allyloxy)benzoate 在 palladium on activated charcoal 吡啶 、 氢气 、 三苯基膦 、 lithium tert-butoxide 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙酸乙酯 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 32.5h， 生成 (1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl (2S)-(4-isopropylphenyl)[(2-methyl-3-oxo-5,7-dipropyl-2,3-dihydro-1,2-benzisoxazol-6-yl)oxy]acetate
  参考文献：
  名称：

  Design and Synthesis of α-Aryloxyphenylacetic Acid Derivatives:  A Novel Class of PPARα/γ Dual Agonists with Potent Antihyperglycemic and Lipid Modulating Activity

  摘要：

  The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.

  DOI：

  10.1021/jm0502135