(S)-2-(3-Cyclohexyl-ureido)-4-methyl-pentanoic acid | 142380-48-1

• 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: (S)-2-(3-Cyclohexyl-ureido)-4-methyl-pentanoic acid
• 英文别名: (2S)-2-(cyclohexylcarbamoylamino)-4-methylpentanoic acid
• CAS: 142380-48-1
• 化学式: C₁₃H₂₄N₂O₃
• mdl: MFCD04196936
• 分子量: 256.345
• InChiKey: PIFSZNCRIBFFQX-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.846
• 拓扑面积：
  78.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-2-(3-Cyclohexyl-ureido)-4-methyl-pentanoic acid 在 N-甲基吗啉 、 lithium hydroxide 、 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 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-[(R)-1-[(S)-2-(3-Cyclohexyl-ureido)-4-methyl-pentanoylamino]-2-(1H-indol-3-yl)-ethyl]-5-methyl-1H-imidazole-4-carboxylic acid
  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-((cyclohexylamino)carbonyl)leucine benzyl ester 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以90%的产率得到(S)-2-(3-Cyclohexyl-ureido)-4-methyl-pentanoic 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

• Controlled Ring Opening of <i>N</i>-Sulfinyl- and <i>N</i>-Silyl-<i>N</i>-carboxyanhydrides (NCA): One-Pot Synthesis of Dipeptides and Unsymmetrical Peptidyl Ureas from Unprotected NCA
  作者：Vincent Levacher、Julia Mateos-Caro、Yves Robin、Francis Marsais

  DOI：10.1055/s-0028-1087510

  日期：——

  We report herein new labile protecting groups of N-carboxyanhydrides (NCA) useful to prevent polymerization during coupling reactions with nitrogen nucleophiles. Thus, N-sulfinyl-NCA 1 and N-silyl-NCA 2 were prepared in situ and involved, without being isolated, in coupling reactions with various α-amino esters to furnish dipeptides 3 and unsymmetrical peptidyl ureas 4, respectively, in good yields.

  我们在此报道了新的N-羧基环内酐（NCA）不稳定保护基团，这些基团在氮亲核试剂参与的偶联反应中能有效防止聚合反应的发生。因此，N-亚砜基NCA 1和N-硅基NCA 2在反应中现场制备，并未分离出来，而是直接与各种α-氨基酯进行偶联反应，分别以良好收率得到了二肽3和不对称肽脲4。
• [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. 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.