2-[(R)-1-Amino-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid benzyl ester | 168470-88-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[(R)-1-Amino-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid benzyl ester
• 英文别名: benzyl 2-[(1R)-1-amino-2-(1-methylindol-3-yl)ethyl]-5-methyl-1,3-oxazole-4-carboxylate
• CAS: 168470-88-0
• 化学式: C₂₃H₂₃N₃O₃
• 分子量: 389.454
• InChiKey: DFPPETQJZHQEBL-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  83.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[(R)-1-Amino-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid benzyl ester 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 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 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 22.0h， 生成 2-[(R)-1-[(S)-2-(3-Cyclohexyl-ureido)-4-methyl-pentanoylamino]-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid
  参考文献：
  名称：

  Azole Endothelin Antagonists. 3. Using Δ log P as a Tool To Improve Absorption

  摘要：

  The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter Delta log P. Comparison of urea 2 with a series of well-absorbed compounds using Delta log P analysis suggested that 2 has an excess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation between Delta log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.

  DOI：

  10.1021/jm9505932
• 作为产物：
  描述：

  2-[(R)-1-tert-Butoxycarbonylamino-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid benzyl ester 在 三氟乙酸 作用下， 反应 1.0h， 生成 2-[(R)-1-Amino-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid benzyl ester
  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+

文献信息

• Azole Endothelin Antagonists. 3. Using Δ log <i>P</i> as a Tool To Improve Absorption
  作者：Thomas W. von Geldern、Daniel J. Hoffman、Jeffrey A. Kester、Hugh N. Nellans、Brian D. Dayton、Samuel V. Calzadilla、Kennan C. Marsh、Lisa Hernandez、William Chiou、Douglas B. Dixon、Jinshyun R. Wu-Wong、Terry J. Opgenorth

  DOI：10.1021/jm9505932

  日期：1996.1.1

  The oral absorption profile of a family of azole-based ET(A)-selective antagonists has been improved through a rational series of structural modifications which were suggested by analysis of the physicochemical parameter Delta log P. Comparison of urea 2 with a series of well-absorbed compounds using Delta log P analysis suggested that 2 has an excess capacity for forming hydrogen bonds with solvent. A series of urea modifications were explored as a means of reducing H-bonding capacity while maintaining affinity for the ET(A)-receptor. The correlation between Delta log P values and absorption in an intraduodenal (id) bioavailability model was good; this strategy uncovered replacements for each of the urea NH groups which simultaneously improve both potency and drug absorption. A combination of these optimized modifications produces carbamate 16h, a highly-selective ET(A) antagonist with a potency/bioavailability profile consistent with an oral route of administration.
• [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.
• [EN] ENDOTHELIN ANTAGONISTS<br/>[FR] ANTAGONISTES DE L'ENDOTHELINE
  申请人：ABBOTT LABORATORIES

  公开号：WO1996011927A1

  公开（公告）日：1996-04-25

  (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 for antagonizing endothelin.(FR) L'invention concerne un composé de la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des procédés de préparation d'un tel composé et les intermédiaires utilisés à cet effet, ainsi que des procédés et des compositions permettant de créer un antagonisme vis-à-vis 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.