2-[(R)-1-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid | 168471-08-7

• 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-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid
• 英文别名: 5-methyl-2-[(1R)-2-(1-methylindol-3-yl)-1-[[(2S)-4-methyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentanoyl]amino]ethyl]-1,3-oxazole-4-carboxylic acid
• CAS: 168471-08-7
• 化学式: C₂₈H₃₈N₄O₆
• 分子量: 526.633
• InChiKey: UMLLVCCRHYCXFQ-IRLDBZIGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  127
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-[(R)-1-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-4-methyl-pentanoylamino]-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid 在 N-甲基吗啉 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成 2-[(R)-1-[(S)-2-(3-Cyclohexyl-1-methyl-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-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 19.0h， 生成 2-[(R)-1-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-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

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.