(S)-3-methyl-2-[(1-pyridin-2-ylmethanoyl)amino]butyric acid | 724733-75-9

• 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)-3-methyl-2-[(1-pyridin-2-ylmethanoyl)amino]butyric acid
• 英文别名: (S)-3-methyl-2-[(pyridine-2-carbonyl)amino]butyric acid；3-methyl-2-[(pyridine-2-carbonyl)amino]butyric acid；picolinoyl-L-valine；(2S)-3-methyl-2-(pyridine-2-carbonylamino)butanoic acid
• CAS: 724733-75-9
• 化学式: C₁₁H₁₄N₂O₃
• mdl: MFCD08444937
• 分子量: 222.244
• InChiKey: TZRRISNEOUTNSA-VIFPVBQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  79.3
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-3-methyl-2-[(1-pyridin-2-ylmethanoyl)amino]butyric acid 在 氨 、 N,N-二异丙基乙胺 、 O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 2.5h， 生成 picolinoyl-L-valylglycinamide
  参考文献：
  名称：

  Synthesis, Pharmacological, and Biological Evaluation of MIF-1 Picolinoyl Peptidomimetics as Positive Allosteric Modulators of D₂R

  摘要：

  This work describes the synthesis and pharmacological evaluation of picolinoyl-based peptidomimetics of melanocyte stimulating hormone release inhibiting factor 1 (MIF-1) as dopamine modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([H-3]-NPA) at dopamine D-2 receptors (D2R). Methyl picolinoyl-L-valyl-L-alaninate (compound 6b) produced a statistically significant increase in the maximal [H-3]-NPA response at 0.01 nM (11.9 +/- 3.7%), which is close to the effect of MIF-1 in this assay at same concentration (18.3 +/- 9.1%). Functional assays measuring cAMP mobilization in the presence of dopamine corroborate the activity of peptidomimetic 6b as a positive allosteric modulator (PAM) of D2R. In this assay, 6b produced a typical bell-shaped dose-response curve similar to that of the parent neuropeptide (18.3 +/- 7.1% for 6b vs 15.4 +/- 5.5% for MIF-1, both at 0.1 nM). Dose-response curves for dopamine in the presence of 6b show EC50 (0.33 +/- 0.21 mu M for 6b vs 0.17 +/- 0.07 pM for MIF-1) and E-max (86.0 +/- 5.4% for 6b vs 93.6 +/- 4.4% for MIF-1) comparable to those of MIF-1, both at 0.01 nM. Furthermore, peptidomimetic 6b was tested for agonist activity at the human D2R and the results show that it displays no intrinsic agonism effect, endorsing its activity as a PAM of D2R. Cytotoxic and neurotoxic assays were performed for peptidomimetic 6b using HEK 293T cells and cortex neurons from 19 day old Wistar-Kyoto rat embryos, respectively, suggesting this analogue displays no toxicity effect in these assays up to 100 mu M. Conformational energy minimization for 6b shows that this peptidomimetic cannot adopt the postulated type-II beta-turn bioactive conformation, endorsing the possibility of an extended bioactive conformation as claimed by other researchers as a second bioactive conformation of MIF-1. Overall, the pharmacological and toxicological profile of peptidomimetic 6b together with its favorable druglike properties and structural simplicity makes it a potential lead compound for further development and optimization.

  DOI：

  10.1021/acschemneuro.9b00259
• 作为产物：
  描述：

  (S)-methyl 3-methyl-2-(picolinamido)butanoate 在 lithium hydroxide monohydrate 、 水 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以92%的产率得到(S)-3-methyl-2-[(1-pyridin-2-ylmethanoyl)amino]butyric acid
  参考文献：
  名称：

  N4-四齿二羧基氨基甲酸酯/二吡啶基钯配合物作为失活芳基氯化物的Heck反应的鲁棒催化剂

  摘要：

  从N4-四齿二羧酰胺/二吡啶基配体衍生的结构明确且热稳定的Pd II复合物被评估为失活的芳基氯化物和烯烃的Heck反应的催化剂（参见方案）。本文证明了使用阴离子羧酰胺作为钯的辅助配体的概念为开发无膦过渡金属催化提供了新的机会。

  DOI：

  10.1002/chem.200802144

文献信息

• [EN] GRANZYME B DIRECTED IMAGING AND THERAPY<br/>[FR] IMAGERIE DU GRANZYME B ET THÉRAPIE DIRIGÉES CONTRE LE GRANZYME B
  申请人：CYTOSITE BIOPHARMA INC

  公开号：WO2019160916A1

  公开（公告）日：2019-08-22

  Provided herein are heterocyclic compounds useful for imaging Granzyme B. Methods of imaging Granzyme B, combination therapies, and kits comprising the Granzyme B imaging agents are also provided.

  本文提供了用于成像Granzyme B的杂环化合物。还提供了成像Granzyme B的方法、联合疗法以及包含Granzyme B成像试剂的试剂盒。
• Mechanism-Based Inhibitors of the Aspartyl Protease Plasmepsin II as Potential Antimalarial Agents
  作者：Deepak Gupta、Ravikiran S. Yedidi、Sheeba Varghese、Ladislau C. Kovari、Patrick M. Woster

  DOI：10.1021/jm100233b

  日期：2010.5.27

  evaluation of reversible peptidomimetic inhibitors of Plm II as potential antimalarial agents. We now report four peptidomimetic analogues, compounds 6−9, which are rationally designed to act as mechanism-based inhibitors of Plm II. Three of these analogues produce potent irreversible inactivation of the enzyme with IC50 values in the low nanomolar range. Of these three compounds, two retain the low micromolar

  四种被称为纤溶酶的天冬氨酰蛋白酶参与了恶性疟原虫对血红蛋白的降解，恶性疟原虫导致大量疟疾死亡。纤溶酶II（Plm II）是这些天冬氨酰蛋白酶中研究最广泛的酶，它催化寄生虫分解血红蛋白的初始步骤。几个研究小组已经报告了Plm II可逆拟肽抑制剂作为潜在抗疟药的设计，合成和评估。我们现在报告4个拟肽类似物，化合物6 - 9，其被合理设计以充当犿II的基于机制的抑制剂。这些类似物中的三种可通过IC 50产生强力的不可逆酶灭活作用值在低纳摩尔范围内。在这三种化合物中，两种保留了恶性疟原虫（克隆3D7）感染的红细胞中母体化合物的低微摩尔IC 50值。这些类似物是天冬氨酰蛋白酶完全表征的基于机制的灭活剂的第一个实例，并显示出作为新型抗疟药的希望。
• Design and Synthesis of Potent Inhibitors of the Malaria Aspartyl Proteases Plasmepsin I and II. Use of Solid-Phase Synthesis to Explore Novel Statine Motifs
  作者：Per-Ola Johansson、Yantao Chen、Anna Karin Belfrage、Michael J. Blackman、Ingemar Kvarnström、Katarina Jansson、Lotta Vrang、Elizabeth Hamelink、Anders Hallberg、Åsa Rosenquist、Bertil Samuelsson

  DOI：10.1021/jm031106i

  日期：2004.6.1

  Picomolar to low nanomolar inhibitors of the two aspartic proteases plasmepsin (Plm) I and II, from the malaria parasite Plasmodium falciparum, have been identified from sets of libraries containing novel statine-like templates modified at the amino and carboxy terminus. The syntheses of the novel statine templates were carried out in solution phase using efficient synthetic routes and resulting in excellent stereochemical control. The most promising statine template was attached to solid support and diversified by use of parallel synthesis. The products were evaluated for their Plm I and II inhibitory activity as well as their selectivity over cathepsin D. Selected inhibitors were, in addition, evaluated for their inhibition of parasite growth in cultured infected human red blood cells. The most potent inhibitor in this report, compound 16, displays K-i values of 0.5 and 2.2 nM for Plm I and II, respectively. Inhibitor 16 is also effective in attenuating parasite growth in red blood cells showing 51% inhibition at a concentration of 5 muM. Several inhibitors have been identified that exhibit K-i values between 0.5 and 74 nM for both Plm I and II. Some of these inhibitors also show excellent selectivity vs cathepsin D.
• GRANZYME B DIRECTED IMAGING AND THERAPY
  申请人：Cytosite Biopharma Inc.

  公开号：EP3752145A1

  公开（公告）日：2020-12-23
• US5756650A
  申请人：——

  公开号：US5756650A

  公开（公告）日：1998-05-26