(S)-tert-butyl 2-((4-cyanobenzyl)carbamoyl)pyrrolidine-1-carboxylate | 179816-47-8

• 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: (S)-tert-butyl 2-((4-cyanobenzyl)carbamoyl)pyrrolidine-1-carboxylate
• 英文别名: Boc-proline (p-cyanobenzyl)amide；tert-butyl (2S)-2-[(4-cyanophenyl)methylcarbamoyl]pyrrolidine-1-carboxylate
• CAS: 179816-47-8
• 化学式: C₁₈H₂₃N₃O₃
• 分子量: 329.399
• InChiKey: ORGUZAVAGHRLHN-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  82.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-tert-butyl 2-((4-cyanobenzyl)carbamoyl)pyrrolidine-1-carboxylate 在 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 盐酸羟胺 、 乙酸酐 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.5h， 生成 tert-butyl ((R)-1-((S)-2-((4-carbamimidoylbenzyl)carbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate
  参考文献：
  名称：

  Binding cooperativity between a ligand carbonyl group and a hydrophobic side chain can be enhanced by additional H-bonds in a distance dependent manner: A case study with thrombin inhibitors

  摘要：

  One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positive cooperativity between an H-bond accepting carbonyl functionality and the adjacent P3 hydrophobic side chain. Adding an H-bond donating amine adjacent to the P3 hydrophobic side chain further increases this positive cooperativity thereby improving the Ki by as much as 546-fold. In contrast, adding an amidine multiple H-bond/salt bridge group in the distal S1 pocket does not affect this cooperativity. An analysis of the crystallographic B-factors of the ligand groups inside the binding site indicates that the strong cooperativity is mainly due to a significant mutual reduction in the residual mobility of the hydrophobic side chain and the H-bonding functionalities that is absent when the separation distance is large. This type of cooperativity is important to encode in binding affinity prediction software, and to consider in SAR studies. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.03.059
• 作为产物：
  描述：

  BOC-L-脯氨酸 、 对氰基苄胺 在 1-丙基磷酸酐 、 N,N-二异丙基乙胺 作用下， 生成 (S)-tert-butyl 2-((4-cyanobenzyl)carbamoyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Orally active thrombin inhibitors. Part 2: Optimization of the P2-moiety

  摘要：

  Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.

  DOI：

  10.1016/j.bmcl.2006.01.046

文献信息

• Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation
  作者：Nader N. Nasief、Ahmed M. Said、David Hangauer

  DOI：10.1016/j.ejmech.2016.09.038

  日期：2017.1

  of hydrogen bonding is a challenging but crucial task to improve our ability to design ligands with high affinity for protein hosts. To gain a deeper understanding of these aspects, we investigated a series of thrombin inhibitors in which the basicity of the ligand's group that accepts an H-bond from Gly216 was modulated via bioisosterism; e.g., a C=O acceptor was made electron deficient or rich via

  理解氢键的细微方面是提高我们设计对蛋白质宿主具有高亲和力的配体的能力的一项艰巨而关键的任务。为了对这些方面有更深入的了解，我们研究了一系列凝血酶抑制剂，其中通过生物立体异构调节了从Gly216接受H键的配体基团的碱性。例如，通过相邻部分的生物等排代换，使C = O受体电子缺乏或富集。尽管当增加H键的碱性时（由于与蛋白质更强的H键结合），预期配体的结合亲和力会提高，但我们在此提供的数据出乎意料地显示出相反的趋势。该趋势归因于去溶剂化在确定相对结合亲和力中的主导作用。例如，H-键碱性的降低减少了去溶剂化损失，并且如实验观察到的，提高了结合亲和力，因为去溶剂化损失的减少主导了配体与蛋白质相互作用的净贡献的变化。因此，当前的研究表明，去溶剂化可能是造成明显的反直觉的结构-活性关系（SAR）结果的主要原因，并且表明了解这一因素可以提高我们预测结合亲和力和设计更有效配体的能力。
• Ligand binding cooperativity: Bioisosteric replacement of CO with SO2 among thrombin inhibitors
  作者：Ahmed M. Said、David G. Hangauer

  DOI：10.1016/j.bmcl.2016.07.024

  日期：2016.8

  Ligand–protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host. Upon binding, ligand functional groups can act synergistically (positive cooperativity) to improve the overall ligand binding affinity beyond what would be expected from their individual contributions. In

  配体与蛋白质的结合是一个复杂的过程，涉及在配体与蛋白质宿主之间形成许多非共价相互作用，例如H键和疏水相互作用。结合后，配体官能团可以协同作用（正协同作用），以提高总体配体结合亲和力，超出其各自贡献的预期范围。在这项研究中，使用凝血酶作为蛋白质模型系统，我们评估了用磺酰基官能团生物等位取代羰基官能团对其与凝血酶的H键之间的正协同作用以及相邻S3口袋中的疏水结合的影响。当用磺酰基取代羰基时，观察到的正协同性大大降低。
• Dipeptide p-amidinobenzylamides with N-terminal sulfonyl or
  申请人：BASF Aktiengesellschaft

  公开号：US05852051A1

  公开（公告）日：1998-12-22

  Compounds of the formula I ##STR1## in which R.sup.1, A and B have the meanings stated in the description, and the preparation thereof are described. The novel compounds are suitable for controlling diseases.

  本发明涉及公式I的化合物，其中R.sup.1，A和B的含义如描述中所述，并描述了其制备方法。这些新化合物适用于控制疾病。
• NEUE THROMBININHIBITOREN, IHRE HERSTELLUNG UND VERWENDUNG
  申请人：BASF AKTIENGESELLSCHAFT

  公开号：EP0773955B1

  公开（公告）日：2003-04-16
• NEUE DIPEPTIDISCHE P-AMIDINOBENZYLAMIDE MIT N-TERMINALEN SULFONYL- BZW. AMINOSULFONYLRESTEN
  申请人：BASF AKTIENGESELLSCHAFT

  公开号：EP0796271A1

  公开（公告）日：1997-09-24