(2S)-4-methyl-2-<<(2S)-2-(1-oxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl>amino>pentanoic acid methyl ester | 137282-11-2

• 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)-4-methyl-2-<<(2S)-2-(1-oxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl>amino>pentanoic acid methyl ester
• 英文别名: methyl (2S)-4-methyl-2-[[(2S)-2-(3-oxo-1H-isoindol-2-yl)-3-phenylpropanoyl]amino]pentanoate
• CAS: 137282-11-2
• 化学式: C₂₄H₂₈N₂O₄
• 分子量: 408.497
• InChiKey: FWCDDSJBIIRWML-SFTDATJTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.96
• 重原子数：
  30.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  75.71
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (2S)-4-methyl-2-<<(2S)-2-(1-oxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl>amino>pentanoic acid methyl ester 在 sodium hydroxide 、 1-环已基-2-吗啉乙基碳二亚胺对甲苯磺酸盐 、 1-羟基苯并三唑 作用下， 以 甲醇 为溶剂， 反应 0.17h， 生成 (3S)-4-cyclohexyl-2-hydroxy-3-<<(2S)-4-methyl-2-<<(2S)-2-(1-oxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl>amino>pentanoyl>amino>butyric acid isopropyl ester
  参考文献：
  名称：

  New modified heterocyclic phenylalanine derivatives. Incorporation into potent inhibitors of human renin

  摘要：

  Modified heterocyclic phenylalanine analogues designed as replacements for the P3-P4 region were synthesized and incorporated into renin inhibitors. These inhibitors were found to have significant activity versus human recombinant renin, as well as in vivo activity. The compounds proved to be very resistant to chymotrypsin degradation, as exemplified by compound 8, which remained greater than 60% intact after a 24-h exposure to chymotrypsin. In contrast, the Boc-Phe analogue was nearly completely degraded after 1 h. Compound 6 proved to be the most potent renin inhibitor with an IC50 = 8.9 nM. These stable cyclized phenylalanines should prove to be generally useful as a substitute for Boc-Phe in protease inhibitors.

  DOI：

  10.1021/jm00083a005
• 作为产物：
  描述：

  L-苯丙氨酸 在 N-甲基吗啉 、 sodium cyanoborohydride 、 氯甲酸异丁酯 作用下， 以 乙酸乙酯 为溶剂， 反应 0.91h， 生成 (2S)-4-methyl-2-<<(2S)-2-(1-oxo-1,3-dihydroisoindol-2-yl)-3-phenylpropionyl>amino>pentanoic acid methyl ester
  参考文献：
  名称：

  New modified heterocyclic phenylalanine derivatives. Incorporation into potent inhibitors of human renin

  摘要：

  Modified heterocyclic phenylalanine analogues designed as replacements for the P3-P4 region were synthesized and incorporated into renin inhibitors. These inhibitors were found to have significant activity versus human recombinant renin, as well as in vivo activity. The compounds proved to be very resistant to chymotrypsin degradation, as exemplified by compound 8, which remained greater than 60% intact after a 24-h exposure to chymotrypsin. In contrast, the Boc-Phe analogue was nearly completely degraded after 1 h. Compound 6 proved to be the most potent renin inhibitor with an IC50 = 8.9 nM. These stable cyclized phenylalanines should prove to be generally useful as a substitute for Boc-Phe in protease inhibitors.

  DOI：

  10.1021/jm00083a005

文献信息

• Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach
  作者：Laurent Hoffer、Manon Garcia、Raphael Leblanc、Mikael Feracci、Stéphane Betzi、Khaoula Ben Yaala、Avais M. Daulat、Pascale Zimmermann、Philippe Roche、Karine Barral、Xavier Morelli

  DOI：10.1021/acs.jmedchem.2c01569

  日期：——

  reactions, constrained docking, and automated compound evaluation. To validate its utility, we applied our DOTS strategy to the challenging target syntenin, a PDZ domain containing protein and oncology target. Herein, we describe the creation of a “best-in-class” sub-micromolar small molecule inhibitor for the second PDZ domain of syntenin validated in cancer cell assays. Key to the success of our DOTS

  通过基于片段的方法快速识别早期命中以及随后的命中到先导优化代表了药物发现的挑战。为了应对这一挑战，我们创建了一种称为“DOTS”的策略，该策略将分子动力学模拟、基于计算机的库设计 (chemoDOTS) 与编码药物化学反应、约束对接和自动化合物评估相结合。为了验证其实用性，我们将我们的 DOTS 策略应用于具有挑战性的目标 syntenin，这是一个包含蛋白质和肿瘤学目标的 PDZ 结构域。在此，我们描述了在癌细胞检测中验证的 syntenin 的第二个 PDZ 结构域的“同类最佳”亚微摩尔小分子抑制剂的创建。我们的 DOTS 方法成功的关键是在命中识别阶段整合蛋白质构象采样，以及在整个优化过程中设计化合物的合成可行性排名。这种方法可以广泛应用于具有已知 3D 结构的其他蛋白质靶标，以快速识别和优化作为化学探针和治疗候选物的化合物。