benzyl (3S)-3-[[(2S)-2-[[(3S,6S,8aS)-5-oxo-6-[(2-phenylacetyl)amino]-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carbonyl]amino]-3-pyridin-3-ylpropanoyl]amino]-4-phenylbutanoate | 1329063-32-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: benzyl (3S)-3-[[(2S)-2-[[(3S,6S,8aS)-5-oxo-6-[(2-phenylacetyl)amino]-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carbonyl]amino]-3-pyridin-3-ylpropanoyl]amino]-4-phenylbutanoate
• CAS: 1329063-32-2
• 化学式: C₄₂H₄₅N₅O₆
• 分子量: 715.849
• InChiKey: MKAOIOXCZXJXTK-LTLCPEALSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  53
• 可旋转键数：
  16
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  147
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  benzyl (3S)-3-[[(2S)-2-[[(3S,6S,8aS)-5-oxo-6-[(2-phenylacetyl)amino]-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carbonyl]amino]-3-pyridin-3-ylpropanoyl]amino]-4-phenylbutanoate 在 palladium 10% on activated carbon 、 氢气 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 以2%的产率得到PDC113.824
  参考文献：
  名称：

  Targeting the Prostaglandin F2α Receptor for Preventing Preterm Labor with Azapeptide Tocolytics

  摘要：

  The prostaglandin-F2 alpha (PGF2 alpha) receptor (FP) was targeted to develop tocolytic agents for inhibiting preterm labor. Azabicycloalkane and azapeptide mimics 2-10 were synthesized based on the (3S,6S,9S)-indolizidin-2-one amino acid analogue PDC113.824 (1), which was shown to modulate FP by a biased allosteric mechanism, involving both G alpha q- and G alpha 12-mediated signaling pathways, and exhibited significant tocolytic activity delaying preterm labor in a mouse model (Goupil; J. Biol. Chem. 2010, 285,25624-25636), Although changes in azabicycloalkane stereochemistry and ring size caused loss of activity, replacement of the indolizidin-2-one amino acid with azaGly-Pro and azaPhe-Pro gave azapeptides 6 and 8, which reduced PGF2 alpha-induced myometrial contractions, potentiated the effect of PGF2 alpha on G alpha q-mediated ERK1/2 activation, and inhibited FP modulation of cell ruffling, a response dependent on the G alpha 12/RhoA/ROCK signaling pathway. Revealing complementarities of azabicycloalkane and azapeptide mimics, novel probes, and efficient tocolytic agents were made to study allosteric modulation of the FP receptor.

  DOI：

  10.1021/jm200608k
• 作为产物：
  描述：

  N-Boc-(2S)-(3-pyridyl)alaninyl-(3S)-β-homophenylalanine benzyl ester 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 15.25h， 生成 benzyl (3S)-3-[[(2S)-2-[[(3S,6S,8aS)-5-oxo-6-[(2-phenylacetyl)amino]-2,3,6,7,8,8a-hexahydro-1H-indolizine-3-carbonyl]amino]-3-pyridin-3-ylpropanoyl]amino]-4-phenylbutanoate
  参考文献：
  名称：

  Targeting the Prostaglandin F2α Receptor for Preventing Preterm Labor with Azapeptide Tocolytics

  摘要：

  The prostaglandin-F2 alpha (PGF2 alpha) receptor (FP) was targeted to develop tocolytic agents for inhibiting preterm labor. Azabicycloalkane and azapeptide mimics 2-10 were synthesized based on the (3S,6S,9S)-indolizidin-2-one amino acid analogue PDC113.824 (1), which was shown to modulate FP by a biased allosteric mechanism, involving both G alpha q- and G alpha 12-mediated signaling pathways, and exhibited significant tocolytic activity delaying preterm labor in a mouse model (Goupil; J. Biol. Chem. 2010, 285,25624-25636), Although changes in azabicycloalkane stereochemistry and ring size caused loss of activity, replacement of the indolizidin-2-one amino acid with azaGly-Pro and azaPhe-Pro gave azapeptides 6 and 8, which reduced PGF2 alpha-induced myometrial contractions, potentiated the effect of PGF2 alpha on G alpha q-mediated ERK1/2 activation, and inhibited FP modulation of cell ruffling, a response dependent on the G alpha 12/RhoA/ROCK signaling pathway. Revealing complementarities of azabicycloalkane and azapeptide mimics, novel probes, and efficient tocolytic agents were made to study allosteric modulation of the FP receptor.

  DOI：

  10.1021/jm200608k

文献信息

• Paired Utility of Aza-Amino Acyl Proline and Indolizidinone Amino Acid Residues for Peptide Mimicry: Conception of Prostaglandin F2α Receptor Allosteric Modulators That Delay Preterm Birth
  作者：Fatemeh M. Mir、N. D. Prasad Atmuri、Carine B. Bourguet、Jennifer Rodon Fores、Xin Hou、Sylvain Chemtob、William D. Lubell

  DOI：10.1021/acs.jmedchem.9b00056

  日期：2019.5.9

  Peptide mimicry employing a combination of aza-amino acyl proline and indolizidinone residues has been used to develop allosteric modulators of the prostaglandin F2α receptor. The systematic study of the N-terminal phenylacetyl moiety and the conformation and side chain functions of the central turn dipeptide residue has demonstrated the sensitive relationships between modulator activity and topology

  利用氮杂-氨基酰基脯氨酸和吲哚izidinone残基的组合模拟肽已被用于开发前列腺素F2α受体的变构调节剂。系统研究N末端苯乙酰基部分和中央转向二肽残基的构象和侧链功能已证明调节剂活性和拓扑之间的敏感关系。在以脂多糖治疗的小鼠早产模型中对aza-Gly-Pro和aza-Phe-Pro类似物2a和2b的检查表明，它们能够显着延长平均分娩时间（> 20小时），从而为延迟早产提供了新的原型。 。