trans,trans-2-[4-(2-methoxyethoxy)phenyl]-4-(1,3-benzodioxol-5-yl)-1-[(2,2-dimethyl-1-phenylpropyl)aminocarbonylmethyl]pyrrolidine-3-carboxylic acid

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: trans,trans-2-[4-(2-methoxyethoxy)phenyl]-4-(1,3-benzodioxol-5-yl)-1-[(2,2-dimethyl-1-phenylpropyl)aminocarbonylmethyl]pyrrolidine-3-carboxylic acid
• 英文别名: (2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-1-[(2,2-dimethyl-1-phenyl-propylcarbamoyl)-methyl]-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-3-carboxylic acid; TFA；(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-[(2,2-dimethyl-1-phenylpropyl)amino]-2-oxoethyl]-2-[4-(2-methoxyethoxy)phenyl]pyrrolidine-3-carboxylic acid
• 化学式: C₃₄H₄₀N₂O₇
• 分子量: 588.701
• InChiKey: WOQBGOSNHKHPRH-DZEKFYGQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  43
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-Bromo-N-(2,2-dimethyl-1-phenyl-propyl)-acetamide 在 sodium hydroxide 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 乙腈 为溶剂， 生成 trans,trans-2-[4-(2-methoxyethoxy)phenyl]-4-(1,3-benzodioxol-5-yl)-1-[(2,2-dimethyl-1-phenylpropyl)aminocarbonylmethyl]pyrrolidine-3-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Activity of a Series of Pyrrolidine-3-carboxylic Acid-Based, Highly Specific, Orally Active ET_B Antagonists Containing a Diphenylmethylamine Acetamide Side Chain

  摘要：

  The endothelin (ET)-B receptor subtype is expressed on vascular endothelial and smooth muscle cells and mediates both vasodilation and vasoconstriction. On the basis of the pharmacophore of the previously reported ETA-specific antagonist 1, (ABT-627), we are reporting the discovery of a novel series of highly specific, orally active ETB receptor antagonists. Replacing the dibutylaminoacetamide group of 1 with a diphenylmethylaminoacetamide group resulted in antagonist 2 with a complete reversal of receptor specificity. Structure-activity relationship studies revealed that ortho-alkylation of the phenyl rings could further increase ETB affinity and also boost the ETA/ETB activity ratio of the resulting antagonists. A similar antagonism selectivity profile could also be achieved when one of the phenyl rings of the acetamide side chain was replaced with an alkyl group, preferably a tert-butyl group,(10h). Combining these features with modification of the a-aryl group of the pyrrolidine core, we have identified a potent antagonist (9k, A-308165) with over 27 000-fold selectivity favoring the ETB receptor and an acceptable pharmacokinetic profile (F = 24%) in rats.

  DOI：

  10.1021/jm990171i