(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester | 1026518-06-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester
• 英文别名: 1-O-tert-butyl 3-O-ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-[4-(2-methoxyethoxy)phenyl]pyrrolidine-1,3-dicarboxylate
• CAS: 1026518-06-8
• 化学式: C₂₈H₃₅NO₈
• 分子量: 513.588
• InChiKey: XSOWHEVNYVEDNO-SDUSCBPUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  92.8
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 乙腈 为溶剂， 反应 1.0h， 生成
  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
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 (2S,3S,4R)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-3-carboxylic acid ethyl ester 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester
  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

文献信息

• 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
  作者：Gang Liu、Natasha S. Kozmina、Martin Winn、Thomas W. von Geldern、William J. Chiou、Douglas B. Dixon、Bach Nguyen、Kennan C. Marsh、Terry J. Opgenorth

  DOI：10.1021/jm990171i

  日期：1999.9.1

  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.