| 1257531-14-8

• 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
• CAS: 1257531-14-8
• 化学式: C₂₈H₄₅N₅O₇
• 分子量: 563.695
• InChiKey: ACTASCMCXSBOLU-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.89
• 重原子数：
  40.0
• 可旋转键数：
  6.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  156.45
• 氢给体数：
  4.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以74.8%的产率得到(2S)-2-amino-3-methyl-N-[3-[(aminoiminomethyl)amino]phenyl]methylbutanamide
  参考文献：
  名称：

  Specificity of a Prodrug-Activating Enzyme hVACVase: The Leaving Group Effect

  摘要：

  Human valacyclovirase (hVACVase) is a prodrug-activating enzyme for amino acid prodrugs including the antiviral drugs valacyclovir and valganciclovir. In hVACVase-catalyzed reactions, the leaving group of the substrate corresponds to the drug moiety of the prodrug, making the leaving group effect essential for the rational design of new prodrugs targeting hVACVase activation. In this study, a series of valine esters, phenylalanine esters, and a valine amide were characterized for the effect of the leaving group on the efficiency of hVACVase-mediated prodrug activation. Except for phenylalanine methyl and ethyl esters, all of the ester substrates exhibited a relatively high specificity constant (k(cat)/K-m), ranging from 850 to 9490 mM(-1).s(-1). The valine amide Val-3-APG exhibited significantly higher K-m and lower k(cat) values compared to the corresponding ester Val-3-HPG, indicating poor specificity for hVACVase. In conclusion, the substrate leaving group has been shown to affect both binding and specific activity of hVACVase-catalyzed activation. It is proposed that hVACVase is an ideal target for a-amino acid ester prodrugs with relatively labile leaving groups while it is relatively inactivate toward amide prodrugs.

  DOI：

  10.1021/mp100300k
• 作为产物：
  描述：

  N,N'-bis-Boc-S-methyl-isothiourea 在 palladium 10% on activated carbon 、 氨 、 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 、 mercury dichloride 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、310.27 kPa 条件下， 反应 14.0h， 生成
  参考文献：
  名称：

  Specificity of a Prodrug-Activating Enzyme hVACVase: The Leaving Group Effect

  摘要：

  Human valacyclovirase (hVACVase) is a prodrug-activating enzyme for amino acid prodrugs including the antiviral drugs valacyclovir and valganciclovir. In hVACVase-catalyzed reactions, the leaving group of the substrate corresponds to the drug moiety of the prodrug, making the leaving group effect essential for the rational design of new prodrugs targeting hVACVase activation. In this study, a series of valine esters, phenylalanine esters, and a valine amide were characterized for the effect of the leaving group on the efficiency of hVACVase-mediated prodrug activation. Except for phenylalanine methyl and ethyl esters, all of the ester substrates exhibited a relatively high specificity constant (k(cat)/K-m), ranging from 850 to 9490 mM(-1).s(-1). The valine amide Val-3-APG exhibited significantly higher K-m and lower k(cat) values compared to the corresponding ester Val-3-HPG, indicating poor specificity for hVACVase. In conclusion, the substrate leaving group has been shown to affect both binding and specific activity of hVACVase-catalyzed activation. It is proposed that hVACVase is an ideal target for a-amino acid ester prodrugs with relatively labile leaving groups while it is relatively inactivate toward amide prodrugs.

  DOI：

  10.1021/mp100300k

文献信息

• Discovery of Potent, Selective, and Short-Acting Peptidic V₂ Receptor Agonists
  作者：Kazimierz Wiśniewski、Steve Qi、John Kraus、Brian Ly、Karthik Srinivasan、Hiroe Tariga、Glenn Croston、Erin La、Halina Wiśniewska、Carlos Ortiz、Régent Laporte、Pierre J.-M. Rivière、Gebhard Neyer、Diane M. Hargrove、Claudio D. Schteingart

  DOI：10.1021/acs.jmedchem.9b00132

  日期：2019.5.23

  short-acting peptidic V2R agonists, we synthesized a series of C-terminally truncated analogues of [Val4]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge. The peptides were evaluated for in vitro potency at the human V2 receptor, selectivity versus the related receptors (human vasopressin 1a receptor, human vasopressin 1b receptor, and human oxytocin receptor), and pharmacokinetic

  加压素类似物去氨加压素（desamino-d-arginine8加压素，dDAVP，1）是一种有效的加压素2（V2）受体激动剂（V2R），已在许多国家/地区被批准用于治疗尿崩症，原发性夜间遗尿症，夜尿症和凝血障碍。由于1主要通过肾脏排泄，因此，与年龄相关的肾脏功能下降会导致消除速度减慢，抗利尿时间延长和低钠血症。为寻找新颖，有效，选择性和短效的肽V2R激动剂，我们合成了[Val4] dDAVP 2的一系列C端截短的类似物，在位置2、3和7处和/或在二硫键处进行了修饰桥。评估了这些肽对人V2受体的体外效能，相对于相关受体的选择性（人血管加压素1a受体，人血管加压素1b受体，和人类催产素受体），以及在啮齿动物和其他高等物种中的药代动力学特征。截短的类似物在V2R上显示出出色的效价，增加了系统清除率，并缩短了大鼠的半衰期。两种化合物19（c（Bua-Cpa-Thi-Val-Asn-Cys）-Pr
• Solid-Phase Parallel Synthesis of a Tetrahydroindazolone Library Containing Three Unique Core Skeletons
  作者：Jonghoon Kim、Heebum Song、Seung Bum Park

  DOI：10.1002/asia.201100145

  日期：2011.8.1

  the regioselective synthesis of a 1‐(hetero)aryl‐3‐substituted tetrahydroindazolone library. The condensation of in situ generated arylhydrazine on solid supports with 2‐acylcyclohexane‐1,3‐diones ensured the efficiency of solid‐phase parallel synthesis. In addition, we introduced three unique core skeletons containing nitrophenyl, anilyl, and pyridyl groups to maximize the molecular diversity through

  我们为1-（杂）芳基-3-取代的四氢吲哚并隆文库的区域选择性合成开发了一种实用的策略。原位生成的芳基肼在固体载体上与2-酰基环己烷-1,3-二酮的缩合确保了固相平行合成的效率。此外，我们引入了三个独特的核心骨架，其中包含硝基苯基，苯甲酰基和吡啶基，以通过在3D化学空间中极性表面的多样化显示来最大化分子多样性。无需进一步纯化即可构建平均纯度为92％的162元药物样四氢吲哚酮文库。