N-tert-butoxycarbonyl-N'-[2-(tert-butoxycarbonylamino)ethyl]aminocarbonyl-S-methylisothiourea | 1432471-09-4

• 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: N-tert-butoxycarbonyl-N'-[2-(tert-butoxycarbonylamino)ethyl]aminocarbonyl-S-methylisothiourea
• CAS: 1432471-09-4
• 化学式: C₁₅H₂₈N₄O₅S
• 分子量: 376.477
• InChiKey: ACIFDYMQQHZSSX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.46
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  118.12
• 氢给体数：
  3.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (R)-N-(4-tert-butoxybenzyl)-Nα-(2,2-diphenylacetyl)ornithinamide 、 N-tert-butoxycarbonyl-N'-[2-(tert-butoxycarbonylamino)ethyl]aminocarbonyl-S-methylisothiourea 在 N,N-二异丙基乙胺 、 mercury dichloride 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 C₄₄H₆₁N₇O₈
  参考文献：
  名称：

  Argininamide-type neuropeptide Y Y₁ receptor antagonists: the nature of N^ω-carbamoyl substituents determines Y₁R binding mode and affinity

  摘要：

  在参考化合物2中，通过较大的残基（例如72）替换羰胺基团（R）强烈影响了Y1R的亲和力。对于非常庞大的羰胺基取代基（例如78），诱导适应对接建议存在一种倒置结合模式。

  DOI：

  10.1039/c9md00538b
• 作为产物：
  描述：

  N-叔丁氧羰基-1,2-乙二胺 在 碳酸氢钠 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 0.58h， 生成 N-tert-butoxycarbonyl-N'-[2-(tert-butoxycarbonylamino)ethyl]aminocarbonyl-S-methylisothiourea
  参考文献：
  名称：

  基于结构的神经肽 Y Y1 受体高亲和力荧光探针设计

  摘要：

  神经肽 YY 1受体 (Y 1 R) 与精氨酰胺型 Y 1 R 选择性拮抗剂 UR-MK299 ( 2 ) 复合的最近结晶开辟了基于结构设计非肽 Y 1 R 配体的新方法。我们设计的新型荧光探针显示出优异的 Y 1 R 选择性，并且与先前描述的荧光 Y 1 R 配体相比，具有更高（~100 倍）的结合亲和力。这是通过将不同的荧光染料通过胺官能化接头连接到2中的二苯乙酰部分来实现的。荧光配体表现出皮摩尔Y 1R 结合亲和力（p K i值为 9.36-9.95）并被证明是 Y 1 R 拮抗剂，如在 Fura-2 钙测定中验证的那样。通过流式细胞仪和基于荧光各向异性的 Y 1 R 结合研究（饱和和竞争结合以及缔合和解离动力学）以及宽场和全内反射荧光 (TIRF) 显微镜证明了探针作为工具化合物的多功能适用性活肿瘤细胞，揭示荧光主要定位于质膜。

  DOI：

  10.1021/acs.jmedchem.1c02033

文献信息

• [³H]UR-PLN196: A Selective Nonpeptide Radioligand and Insurmountable Antagonist for the Neuropeptide Y Y₂ Receptor
  作者：Nikola Pluym、Paul Baumeister、Max Keller、Günther Bernhardt、Armin Buschauer

  DOI：10.1002/cmdc.201200566

  日期：2013.4

  Radioing in on NPY: Attachment of a [2,3‐3H]propionyl group through an appropriate linker to the guanidine group of an (S)‐argininamide‐type neuropeptide Y (NPY) Y2 receptor antagonist resulted in a subtype‐selective radioligand.

  Radioing在NPY：一个[2,3-的附件3通过适当的连接体与胍基的（的H]丙酰基小号）-argininamide型神经肽Y（NPY）Y 2受体拮抗剂导致了亚型选择性放射性配体。
• Monitoring the Reversibility of GPCR Signaling by Combining Photochromic Ligands with Label‐free Impedance Analysis.
  作者：Ulrike Wirth、Julia Erl、Saphia Azzam、Carina Hoering、Michael Skiba、Ritu Singh、Kathrin Hochmuth、Max Keller、Joachim Wegener、Burkhard Koenig

  DOI：10.1002/anie.202215547

  日期：——

  Combining photochromic agonists of GPCR receptors with label-free impedance analysis of cells expressing this receptor allows monitoring and controlling dynamics and reversibility of intracellular signaling cascades in real time.

  将 GPCR 受体的光致变色激动剂与表达该受体的细胞的无标记阻抗分析相结合，可以实时监测和控制细胞内信号级联的动力学和可逆性。
• Dimeric argininamide-type neuropeptide Y receptor antagonists: Chiral discrimination between Y1 and Y4 receptors
  作者：Max Keller、Melanie Kaske、Tobias Holzammer、Günther Bernhardt、Armin Buschauer

  DOI：10.1016/j.bmc.2013.08.065

  日期：2013.11

  The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R, R)-49): K-i = 230 nM (Y1R) and 290 nM (Y4R)). With a Ki value of 130 nM and a K-b value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S, S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S, S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R, R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists. (C) 2013 Elsevier Ltd. All rights reserved.
• M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding
  作者：Max Keller、Christian Tränkle、Xueke She、Andrea Pegoli、Günther Bernhardt、Armin Buschauer、Roger W. Read

  DOI：10.1016/j.bmc.2015.01.015

  日期：2015.7

  A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [H-3]N-methylscopolamine ([H-3]NMS) at the muscarinic receptor subtype M-2, and seven selected compounds were additionally investigated at M-1, M-3, M-4 and M-5 with respect to receptor subtype selectivity. The side chain of the known M-2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [H-3]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M-2 > M-1 approximate to M-4 > M-3 approximate to M-5 (46, 50, 57, 62-64) and M-2 > M-1 approximate to M-4 > M-3 > M-5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M-2 receptor affinities (pIC(50) = 9.0 and 9.2, respectively). At the M-2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC(50,diss), an estimate of affinity to the allosteric site of M-2 receptors occupied with [H-3]NMS. Compounds 58 and 62-64 were capable of retarding [H-3]NMS dissociation by a factor > 10 (E-max,E-diss >92%), with highest potency (pEC(50,diss) = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC(50),(diss) = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding. (C) 2015 Elsevier Ltd. All rights reserved.
• N^ω-Carbamoylation of the Argininamide Moiety: An Avenue to Insurmountable NPY Y₁ Receptor Antagonists and a Radiolabeled Selective High-Affinity Molecular Tool ([³H]UR-MK299) with Extended Residence Time
  作者：Max Keller、Stefan Weiss、Christoph Hutzler、Kilian K. Kuhn、Catherine Mollereau、Stefanie Dukorn、Lisa Schindler、Günther Bernhardt、Burkhard König、Armin Buschauer

  DOI：10.1021/acs.jmedchem.5b00925

  日期：2015.11.25

  Analogues of the argininamide-type NPY Y-1 receptor (Y1R) antagonist BIBP3226, bearing carbamoyl moieties at the guanidine group, revealed subnanomolar Ki values and caused depression of the maximal response to NPY (calcium assay) by up to 90% in a concentration- and time-dependent manner, suggesting insurmountable antagonism. To gain insight into the mechanism of binding of the synthesized compounds, a tritiated antagonist, (R)-N-a-diphenylacetyl-N-omega-[2-([2,3-H-3]propionylamino)ethyl]aminocarbonyl-(4-hydroxybenzyl)arginin-amide ([H-3]UR-MK299, [H-3]38), was prepared. [H-3]38 revealed a dissociation constant in the picomolar range (K-d 0.044 nM, SK-N-MC cells) and very high Y1R selectivity. Apart from superior affinity, a considerably lower target off-rate (t1/2 95 min) was characteristic of [H-3]38 compared to that of the higher homologue containing a tetramethylene instead of an ethylene spacer (t(1/2) 3 min, K-d 2.0 nM). Y1R binding of [H-3]38 was fully reversible and fully displaceable by nonpeptide antagonists and the agonist pNPY. Therefore, the insurmountable antagonism observed in the functional assay has to be attributed to the extended target-residence time, a phenomenon of relevance in drug research beyond the NPY receptor field.