(3R,S,4S)-((4-N-tert-butoxycarbonyl)amino)-2,2-difluoro-3-hydroxypentanoic acid ethyl ester | 200810-94-2

• 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: (3R,S,4S)-((4-N-tert-butoxycarbonyl)amino)-2,2-difluoro-3-hydroxypentanoic acid ethyl ester
• 英文别名: ethyl (4S)-2,2-difluoro-3-hydroxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoate
• CAS: 200810-94-2
• 化学式: C₁₂H₂₁F₂NO₅
• 分子量: 297.299
• InChiKey: RQNPHHQJPXLSPW-JAMMHHFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  20
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R,S,4S)-((4-N-tert-butoxycarbonyl)amino)-2,2-difluoro-3-hydroxypentanoic acid ethyl ester 在 lithium hydroxide 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.0h， 生成 [4(S)-[[(N-tert-butoxycarbonyl)-L-valyl]amino-2,2-difluoro-3-oxopentanoyl]-L-valyl]-L-isoleucine methyl ester
  参考文献：
  名称：

  二氟酮类肽模拟物提示阿尔茨海默氏病的γ-分泌酶有较大的S1口袋：这对抑制剂设计具有重要意义。

  摘要：

  与阿尔茨海默氏病的病因有关的淀粉样β蛋白（Abeta）的生成的最后一步是通过γ-分泌酶在淀粉样前体蛋白（APP）的跨膜区域内进行蛋白水解。尽管γ-分泌酶被认为是治疗设计的重要目标，但尚未被充分表征或确定。我们实验室中先前使用基于底物的二氟酮和二氟醇过渡态类似物抑制剂的研究表明，γ-分泌酶是天冬氨酰蛋白酶，具有宽松的序列特异性。为了进一步表征γ-分泌酶的活性位点，我们制备了一系列在P1位置具有不同空间体积的二氟酮肽类似物，并测试了这些化合物抑制APP转染细胞中Abeta产生的能力。庞大的脂肪族P1侧链（如仲丁基或环己基甲基）的引入导致增加的γ-分泌酶抑制能力，这表明一个大的S1口袋可容纳这些取代基，并为松散的序列特异性提供了进一步的证据。环己基甲基P1取代基可将N端截短为低分子量化合物（<600 Da），该化合物有效地阻断了Abeta的产生（IC（50）约为5 microM）。该发现表明，最

  DOI：

  10.1021/jm000100f
• 作为产物：
  描述：

  N-叔丁氧羰基-L-丙氨酸 在 lithium aluminium tetrahydride 、 N,N-二异丙基乙胺 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 18.17h， 生成 (3R,S,4S)-((4-N-tert-butoxycarbonyl)amino)-2,2-difluoro-3-hydroxypentanoic acid ethyl ester
  参考文献：
  名称：

  Rational design of the first difluorostatone-based PfSUB1 inhibitors

  摘要：

  The etiological agent of the most dangerous form of malaria, Plasmodium falciparum, has developed resistance or reduced sensitivity to the majority of the drugs available to treat this deadly disease. Innovative antimalarial therapies are therefore urgently required. P. falciparum serine protease subtilisin-like protease 1 (PfSUB1) has been identified as a key enzyme for merozoite egress from red blood cells and invasion. We present herein the rational design, synthesis, and biological evaluation of novel and potent difluorostatone-based inhibitors. Our bioinformatic-driven studies resulted in the identification of compounds 1a, b as potent and selective PfSUB1 inhibitors. The enzyme/inhibitor interaction pattern herein proposed will pave the way to the future optimization of this class of promising enzyme inhibitors. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.05.044

文献信息

• Plasmodium falciparum subtilisin-like protease 1: discovery of potent difluorostatone-based inhibitors
  作者：Simone Giovani、Maria Penzo、Stefania Butini、Margherita Brindisi、Sandra Gemma、Ettore Novellino、Giuseppe Campiani、Michael J. Blackman、Simone Brogi

  DOI：10.1039/c5ra01170a

  日期：——

  available drugs to treat malaria are often ineffective due to the acquisition of drug resistance. In this context, drugs with innovative modes of action and no liability to cross-resistance are urgently needed. Recently, subtilisin-like protease 1, a P. falciparum serine protease involved in merozoite egress from red blood cells and invasion, has been identified as potential drug target. We describe

  由于获得抗药性，目前可用于治疗疟疾的药物通常无效。在这种情况下，迫切需要具有创新作用方式且对交叉耐药性不承担责任的药物。最近，枯草杆菌蛋白酶样蛋白酶1，一种恶性疟原虫丝氨酸蛋白酶，参与了裂殖子从红细胞中逸出并侵入，已被确定为潜在的药物靶标。我们在本文中描述了一系列有效的PfSUB1抑制剂的开发。结合简单的合成方法，深入的结构活性研究和计算机模拟研究，我们确定了迄今为止已知的最有效的抑制剂，其特征在于与原型肽相比，具有更高的酶抑制能力和降低的肽特性。
• Peptidomimetic Inhibitors of the Human Cytomegalovirus Protease
  作者：William Ogilvie、Murray Bailey、Marc-André Poupart、Abraham、Amit Bhavsar、Pierre Bonneau、Josée Bordeleau、Yves Bousquet、Catherine Chabot、Jean-Simon Duceppe、Gulrez Fazal、Sylvie Goulet、Chantal Grand-Maître、Ingrid Guse、Ted Halmos、Pierre Lavallée、Michael Leach、Eric Malenfant、Jeff O'Meara、Raymond Plante、Céline Plouffe、Martin Poirier、François Soucy、Christiane Yoakim、Robert Déziel

  DOI：10.1021/jm970104t

  日期：1997.12.1

  The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) :protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency cf 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P-1 were well tolerated by this enzyme, a fact consistent with previous observations. The S-2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P-3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and a-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P-1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.
• MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
  申请人：RQX PHARMACEUTICALS, INC.

  公开号：US20170088582A1

  公开（公告）日：2017-03-30

  Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
• [EN] MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS<br/>[FR] ANTIBIOTIQUES MACROCYCLIQUES À LARGE SPECTRE
  申请人：RQX PHARMACEUTICALS INC

  公开号：WO2015179441A2

  公开（公告）日：2015-11-26

  Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.