2-[(R)-1-{(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoylamino}-2-(1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid ethyl ester | 168469-29-2

• 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: 2-[(R)-1-{(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoylamino}-2-(1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid ethyl ester
• 英文别名: ethyl 2-[(1R)-1-[[(2S)-2-(azepane-1-carbonylamino)-4-methylpentanoyl]amino]-2-(1H-indol-3-yl)ethyl]-5-methyl-1,3-oxazole-4-carboxylate
• CAS: 168469-29-2
• 化学式: C₃₀H₄₁N₅O₅
• 分子量: 551.686
• InChiKey: QFKWZKDBLRTVOS-LOSJGSFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  130
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-[(R)-1-{(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoylamino}-2-(1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid ethyl ester 在 lithium hydroxide 、 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 1.5h， 生成 2-[(R)-1-{(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoylamino}-2-(1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carbonyl chloride
  参考文献：
  名称：

  Azole Endothelin Antagonists. 2. Structure−Activity Studies

  摘要：

  Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N-Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.

  DOI：

  10.1021/jm950592+
• 作为产物：
  描述：

  N-苄氧羰基-D-色氨酸 在 palladium on activated charcoal N-甲基吗啉 、 吡啶 、 四氯化碳 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 40.5h， 生成 2-[(R)-1-{(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoylamino}-2-(1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  Azole Endothelin Antagonists. 1. A Receptor Model Explains an Unusual Structure−Activity Profile

  摘要：

  The pseudotetrapeptide FR-139317 is a potent and highly selective antagonist of the endothelin-A (ET(A)) receptor; however, its peptidic nature leads to poor oral absorption characteristics which make it an unlikely drug candidate. In an attempt to improve these properties, we have replaced a portion of the amide bond framework of FR-139317 with a heterocyclic surrogate. The resultant analogs are also ET(A)-selective antagonists, but show a structure-activity profile substantially different from that of the peptidic series, particularly with regard to the requirements for the side chain group that has been incorporated into the heterocycle. The nature of the heterocycle itself also has profound effects on the activity of the compounds. Both of these surprising results can be rationalized through examination of a 3D model of ET ligand-receptor binding that has previously been developed in our laboratories.

  DOI：

  10.1021/jm950591h

文献信息

• [EN] ENDOTHELIN ANTAGONISTS<br/>[FR] ANTAGONISTES D'ENDOTHELINE
  申请人：ABBOTT LABORATORIES

  公开号：WO1995008550A1

  公开（公告）日：1995-03-30

  (EN) A compound of formula (I) or a pharmaceutically acceptable salt thereof, as well as processes for and intermediates in the preparation thereof, and methods and compositions of antagonizing endothelin.(FR) Composé représenté par la formule (I), ou un de ses sels pharmaceutiquement acceptable, ainsi que procédés et intermédiaires servant à leur préparation, procédés et compositions antagonistes de l'endothéline.
• Azole Endothelin Antagonists. 2. Structure−Activity Studies
  作者：Thomas W. von Geldern、Jeffrey A. Kester、Radhika Bal、Jinshyun R. Wu-Wong、William Chiou、Douglas B. Dixon、Terry J. Opgenorth

  DOI：10.1021/jm950592+

  日期：1996.1.1

  Structure-activity studies have been performed in an attempt to improve the potency of a novel series of azole-based endothelin-A (ET(A)) selective antagonists. Modifications of the hydrophobic group on the terminal urea produced substantial effects on receptor affinity; in particular, the choice of cyclohexyl- or arylureas led to substantial improvements in activity. Conformational restriction of these groups provides an additional benefit. N-Methylation of the indole moiety which is part of the heterocyclic dipeptide surrogate also improves potency. The effects of these two modifications appear to be synergistic, with the best of the resultant doubly modified analogs (e.g. 14q, 15y, and 15ff) exhibiting an 80-200-fold improvement over the original leads.
• Azole Endothelin Antagonists. 1. A Receptor Model Explains an Unusual Structure−Activity Profile
  作者：Thomas W. von Geldern、Charles Hutchins、Jeffrey A. Kester、Jinshyun R. Wu-Wong、William Chiou、Douglas B. Dixon、Terry J. Opgenorth

  DOI：10.1021/jm950591h

  日期：1996.1.1

  The pseudotetrapeptide FR-139317 is a potent and highly selective antagonist of the endothelin-A (ET(A)) receptor; however, its peptidic nature leads to poor oral absorption characteristics which make it an unlikely drug candidate. In an attempt to improve these properties, we have replaced a portion of the amide bond framework of FR-139317 with a heterocyclic surrogate. The resultant analogs are also ET(A)-selective antagonists, but show a structure-activity profile substantially different from that of the peptidic series, particularly with regard to the requirements for the side chain group that has been incorporated into the heterocycle. The nature of the heterocycle itself also has profound effects on the activity of the compounds. Both of these surprising results can be rationalized through examination of a 3D model of ET ligand-receptor binding that has previously been developed in our laboratories.