(2S)-(3-pyridyl)alaninyl-(3S)-β-homophenylalanine benzyl ester hydrochloride | 1329063-38-8

• 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: (2S)-(3-pyridyl)alaninyl-(3S)-β-homophenylalanine benzyl ester hydrochloride
• 英文别名: benzyl (3S)-3-[[(2S)-2-amino-3-pyridin-3-ylpropanoyl]amino]-4-phenylbutanoate;hydrochloride
• CAS: 1329063-38-8
• 化学式: C₂₅H₂₇N₃O₃*ClH
• 分子量: 453.969
• InChiKey: KCKKMPGGXWGBOL-SJEIDVEUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.23
• 重原子数：
  32
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  94.3
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S)-(3-pyridyl)alaninyl-(3S)-β-homophenylalanine benzyl ester hydrochloride 在 盐酸 、 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 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 0.17h， 生成 phenylacetyl-aza-glycinyl-(2S)-prolyl-(2S)-3-pyridinylalaninyl-(3S)-β-homophenylalanine
  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：

  溴甲苯 在 1-羟基苯并三唑 、 caesium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 6.25h， 生成 (2S)-(3-pyridyl)alaninyl-(3S)-β-homophenylalanine benzyl ester hydrochloride
  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

• Investigation of the active turn geometry for the labour delaying activity of indolizidinone and azapeptide modulators of the prostaglandin F_2α receptor
  作者：Meriem K. Boukanoun、Xin Hou、Ljiljana Nikolajev、Sara Ratni、David Olson、Audrey Claing、Stéphane A. Laporte、Sylvain Chemtob、William D. Lubell

  DOI：10.1039/c5ob00962f

  日期：——

  The bioactive turn geometry of prostaglandin F_2α receptor modulators was investigated in pursuit of molecules that delay labor.

  前列腺素F2α受体调节剂的生物活性转向几何结构被研究，以寻找延迟分娩的分子。
• 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。 。
• 6-Hydroxymethyl Indolizidin-2-one Amino Acid Synthesis, Conformational Analysis, and Biomedical Application as Dipeptide Surrogates in Prostaglandin-F_2α Modulators
  作者：Ramakotaiah Mulamreddy、Xin Hou、Sylvain Chemtob、William D. Lubell

  DOI：10.1021/acs.orglett.1c01733

  日期：2021.7.2

  6-Hydroxymethyl indolizidin-2-one amino acids were synthesized in 10 steps from l-serine by intramolecular ring opening of a symmetrical epoxide and lactam formation. X-ray analyses indicated the bicycles replicated ideal peptide type II′ β-turn central dihedral angle geometry. Inside a prostaglandin-F2α receptor modulator, the 6-hydroxymethyl analogue retained inhibitory activity on myometrial contractility

  6-Hydroxymethyl indolizidin-2-one 氨基酸是从l-丝氨酸通过对称环氧化物和内酰胺形成的分子内开环在 10 个步骤中合成的。X 射线分析表明自行车复制了理想的肽类型 II' β 转中心二面角几何形状。在前列腺素-F 2α受体调节剂中，6-羟甲基类似物保留了对子宫肌层收缩的抑制活性。
• Synthesis of 5‐ and 7‐hydroxy indolizidin‐2‐one prostaglandin‐F _2α modulators and activity on myometrial contractility towards development of agents for delaying preterm birth
  作者：Ramakotaiah Mulamreddy、Xin Hou、Sylvain Chemtob、William D. Lubell

  DOI：10.1002/psc.3455

  日期：2023.3

  In pursuit of more effective‐labor delaying tocolytic agents, the prostaglandin F2α (PGF2α) receptor (FP) modulator PDC113.824 [(6S)‐2] represents a potent lead for developing therapy to treat preterm birth. Derivatives of FP modulator (6S)‐2 were synthesized, possessing respectively 5‐ and 7‐hydroxyl groups on the indolizidin‐2‐one amino acid (I2aa) residue. The effects of the alcohol substituents were examined in a PGF2α‐induced myometrial contraction assay. Based on knowledge of dihedral angle values of model I2aa peptides from X‐ray analyses, the results of the study indicate respectively encouraging and limited potential for creating improved tocolytic agents by modifications at the 5‐ and 7‐positions.