ethyl 4-(2-methylphenyl)-4-[2-(1H-pyrazol-5-yl)-5-(thiophen-3-ylmethoxy)phenoxy]butanoate | 170280-51-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 4-(2-methylphenyl)-4-[2-(1H-pyrazol-5-yl)-5-(thiophen-3-ylmethoxy)phenoxy]butanoate
• CAS: 170280-51-0
• 化学式: C₂₇H₂₈N₂O₄S
• 分子量: 476.596
• InChiKey: GBFOZQSAVSUUEQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  34
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 4-(2-methylphenyl)-4-[2-(1H-pyrazol-5-yl)-5-(thiophen-3-ylmethoxy)phenoxy]butanoate 在 氢氧化钾 作用下， 以 甲醇 为溶剂， 反应 0.5h， 生成 4-[2-(1H-Pyrazol-3-yl)-5-(thiophen-3-ylmethoxy)-phenoxy]-4-o-tolyl-butyric acid
  参考文献：
  名称：

  Selective Endothelin A Receptor Antagonists. 3. Discovery and Structure−Activity Relationships of a Series of 4-Phenoxybutanoic Acid Derivatives

  摘要：

  The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.

  DOI：

  10.1021/jm9707131
• 作为产物：
  描述：

  2,4-二羟基苯乙酮 在 四丁基溴化铵 、 sodium hydride 、 potassium carbonate 、 一水合肼 、 溶剂黄146 、 potassium iodide 作用下， 以 乙醇 、 甲苯 、 丁酮 为溶剂， 反应 71.5h， 生成 ethyl 4-(2-methylphenyl)-4-[2-(1H-pyrazol-5-yl)-5-(thiophen-3-ylmethoxy)phenoxy]butanoate
  参考文献：
  名称：

  Selective Endothelin A Receptor Antagonists. 3. Discovery and Structure−Activity Relationships of a Series of 4-Phenoxybutanoic Acid Derivatives

  摘要：

  The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.

  DOI：

  10.1021/jm9707131

文献信息

• SUBSTITUTED PHENYL COMPOUNDS
  申请人：RHONE-POULENC RORER LIMITED

  公开号：EP0728128B1

  公开（公告）日：1998-09-16