L-N3-Nle-OH

• 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: L-N3-Nle-OH
• 英文别名: (S)-2-azidohexanoic acid；azido-nor-leucine；Diazonorleucine；(2S)-2-azidohexanoic acid
• 化学式: C₆H₁₁N₃O₂
• 分子量: 157.172
• InChiKey: WJWCWIMVMYWVNZ-YFKPBYRVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  11
• 可旋转键数：
  5
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  51.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  L-N3-Nle-OH 在 N-甲基吗啉 作用下， 以 四氢呋喃 为溶剂， 生成 (S)-3-azido-1-bromoheptan-2-one
  参考文献：
  名称：

  Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas’ disease

  摘要：

  Inhibition of the cysteine protease cruzain from Trypanosoma cruzi has been studied pre-clinically as a new chemotherapeutic approach to treat Chagas' disease. Efficacious effects of vinylsulfone-based cruzain inhibitors in animal models support this therapeutic hypothesis. More recently, substrate-activity screening was used to identify nonpeptidic tetrafluorophenoxymethyl ketone inhibitors of cruzain that showed promising efficacy in animal models. Herein we report efforts to further optimize the in vitro potency and in vivo pharmacokinetic properties of this new class of cruzain inhibitors. Through modifications of the P1, P2 and/or P3 positions, new analogs have been identified with reduced lipophilicity, enhanced potency, and improved oral exposure and bioavailability. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.06.066
• 作为产物：
  描述：

  L-正亮氨酸 在 1H-咪唑-1-磺酰叠氮盐酸盐 、 copper(ll) sulfate pentahydrate 、 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 18.0h， 以100%的产率得到L-N3-Nle-OH
  参考文献：
  名称：

  1,2,3-三唑类化合物作为酰胺键模拟物：三唑类扫描产生抗蛋白酶的拟肽模拟肿瘤

  摘要：

  三唑的作用与众不同：用1,4-二取代的1,2,3-三唑等位基因取代肽主链中的酰胺键可提供拟肽，具有保留的受体亲和力和细胞内在化特性，增强了蛋白水解的稳定性，并改善了肿瘤靶向性能力。

  DOI：

  10.1002/anie.201303108

文献信息

• Substrate Activity Screening:  A Fragment-Based Method for the Rapid Identification of Nonpeptidic Protease Inhibitors
  作者：Warren J. L. Wood、Andrew W. Patterson、Hiroyuki Tsuruoka、Rishi K. Jain、Jonathan A. Ellman

  DOI：10.1021/ja0547230

  日期：2005.11.1

  A new fragment-based method for the rapid development of novel and distinct classes of nonpeptidic protease inhibitors, Substrate Activity Screening (SAS), is described. This method consists of three steps: (1) a library of N-acyl aminocoumarins with diverse, low molecular weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay, (2) the identified N-acyl

  描述了一种新的基于片段的方法，用于快速开发新型和不同类别的非肽蛋白酶抑制剂，即底物活性筛选 (SAS)。该方法由三个步骤组成：(1) 筛选具有多种低分子量 N-酰基的 N-酰基氨基香豆素库，以使用简单的基于荧光的测定来鉴定蛋白酶底物，(2) 已鉴定的 N-酰基氨基香豆素底物通过快速类似物合成和评估进行优化，并且 (3) 优化的底物通过用已知机制的药效团直接替换氨基香豆素而转化为抑制剂。SAS 方法已成功应用于与自身免疫性疾病有关的半胱氨酸蛋白酶组织蛋白酶 S。在筛选 N-酰基氨基香豆素文库时鉴定出多种不同类别的非肽底物。两种非肽底物类别针对底物进行了优化，每个类别的切割效率提高了 8000 倍以上。然后将选择的非肽底物直接转化为对组织蛋白酶 S 具有纳摩尔亲和力的低分子量新型醛抑制剂。本研究证明了这种基于底物的快速鉴定和优化弱片段方法的独特特征和优点，并提供了框架用于开发针对许多不同蛋白酶的完全非肽抑制剂。
• Identification of a New Class of Nonpeptidic Inhibitors of Cruzain
  作者：Katrien Brak、Patricia S. Doyle、James H. McKerrow、Jonathan A. Ellman

  DOI：10.1021/ja710254m

  日期：2008.5.1

  inhibitors. The previously unexplored beta-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group p K a, with 2,3,5,6-tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation

  Cruzain 是克氏锥虫的主要半胱氨酸蛋白酶，它是南美锥虫病的病原体，是开发新化疗的有希望的靶点。为了开发有效的 cruzain 非肽抑制剂，使用底物活性筛选 (SAS) 方法筛选最初设计用于靶向同源人蛋白酶组织蛋白酶 S 的蛋白酶底物库。接下来使用基于结构的设计来进一步改进底物通过在 cruzain 的 S3 口袋中引入额外的结合相互作用来提高切割效率。然后通过引入基于半胱氨​​酸蛋白酶机制的药效团将优化的底物转化为抑制剂。抑制剂 38 被确定是可逆的，即使它掺入了乙烯基砜药效团，该药效团已被充分证明可以对肽抑制剂产生不可逆的 cruzain 抑制作用。先前未探索的 β-氯乙烯基砜药效团提供了导致开发有效的不可逆酰基和芳基氧甲基酮 cruzain 抑制剂的机理洞察力。对于这些抑制剂，效力不仅仅取决于离去基团 p K a，2,3,5,6-四氟苯氧基甲基酮 54 被鉴定为最有效的抑制剂之一，其二级失活常数为
• Exploration of cathepsin S inhibitors characterized by a triazole P1–P2 amide replacement
  作者：Neil Moss、Zhaoming Xiong、Mike Burke、Derek Cogan、Donghong A. Gao、Kathleen Haverty、Alexander Heim-Riether、Eugene R. Hickey、Raj Nagaraja、Matthew Netherton、Kathy O’Shea、Philip Ramsden、Racheline Schwartz、Daw-Tsun Shih、Yancey Ward、Erick Young、Qing Zhang

  DOI：10.1016/j.bmcl.2012.09.054

  日期：2012.12

  This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors. (C) 2012 Elsevier Ltd. All rights reserved.
• [EN] NONPEPTIDIC INHIBITORS OF CRUZAIN<br/>[FR] INHIBITEURS NON PEPTIDIQUES DE LA CRUAZÏNE
  申请人：UNIV CALIFORNIA

  公开号：WO2009075778A3

  公开（公告）日：2009-10-15
• Nonpeptidic Tetrafluorophenoxymethyl Ketone Cruzain Inhibitors as Promising New Leads for Chagas Disease Chemotherapy
  作者：Katrien Brak、Iain D. Kerr、Kimberly T. Barrett、Nobuhiro Fuchi、Moumita Debnath、Kenny Ang、Juan C. Engel、James H. McKerrow、Patricia S. Doyle、Linda S. Brinen、Jonathan A. Ellman

  DOI：10.1021/jm901633v

  日期：2010.2.25

  A century after discovering that file Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug, resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor Substantially ameliorates symptoms of acute Chagas disease in a mouse model With no apparent toxicity. A high-resolution Crystal Structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues With improvements in potency despite minimal or no additions in molecular weight. Evaluation Of file analogues in cell Culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the Potential to fulfill file Urgent need for improved Chagas disease chemotherapy.