(2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-3-carboxylic acid ethyl ester | 246853-86-1

• 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-3-carboxylic acid ethyl ester
• 英文别名: ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-[4-(2-methoxyethoxy)phenyl]pyrrolidine-3-carboxylate
• CAS: 246853-86-1
• 化学式: C₂₃H₂₇NO₆
• 分子量: 413.47
• InChiKey: IPUYDLYBGMSXBS-QIJUGHKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  30
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  75.2
• 氢给体数：
  1
• 氢受体数：
  7

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-3-carboxylic acid ethyl ester 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-(N-[2,6-diethylphenyl]acetamido)-pyrrolidino-3-carboxylic acid
  参考文献：
  名称：

  Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists. 4. Side Chain Conformational Restriction Leads to ET_B Selectivity

  摘要：

  When the dialkylacetamide side chain of the ETA-selective antagonist ABT-627 is replaced with a 2,6-dialkylacetanilide, the resultant analogues show a complete reversal of receptor selectivity, preferring ETB over ETA. By optimizing the aniline substitution pattern, as well as the alkoxy group on the 2-aryl substituent, it is possible to prepare antagonists with subnanomolar affinity for ETB and with selectivities in excess of 4000-fold. A number of these compounds also show promising pharmacokinetic profiles; a useful balance of properties is found in A-192621 (38). Pharmacology studies with A-192621 serve to reveal the role of the ETB receptor in modulating blood pressure; the observed hypertensive response to persistent ETB blockade is consistent with previous postulates and indicates that ETB-selective antagonists may not be suitable as agents for long-term systemic therapy.

  DOI：

  10.1021/jm990170q
• 作为产物：
  描述：

  (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 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 (2R,3R,4S)-4-Benzo[1,3]dioxol-5-yl-2-[4-(2-methoxy-ethoxy)-phenyl]-pyrrolidine-3-carboxylic acid 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