(alphaR)-alpha-[(3S)-3-(叔-丁基氧羰基氨基)-4-甲基-2-氧代戊基]-4-氟-苯丙酸 | 223526-67-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 中文名称: (alphaR)-alpha-[(3S)-3-(叔-丁基氧羰基氨基)-4-甲基-2-氧代戊基]-4-氟-苯丙酸
• 英文名称: (2R,5S)-5-(tert-butoxycarbonylamino)-2-(4-fluorobenzyl)-6-methyl-4-oxoheptanic acid
• 英文别名: (2R,5S)-2-[(4-Fluorophenyl)methyl]-6-methyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxoheptanoic acid
• CAS: 223526-67-8
• 化学式: C₂₀H₂₈FNO₅
• 分子量: 381.444
• InChiKey: LEHQDGMPPNTUIE-PBHICJAKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  92.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (alphaR)-alpha-[(3S)-3-(叔-丁基氧羰基氨基)-4-甲基-2-氧代戊基]-4-氟-苯丙酸 在 N-甲基吗啉 、 盐酸 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成
  参考文献：
  名称：

  Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters

  摘要：

  The proteolytic processing of polyproteins by the 3CL protease of severe acute respiratory syndrome coronavirus is essential for the viral propagation. A series of tripeptide alpha,beta-unsaturated esters and ketomethylene isosteres, including AG7088, are synthesized and assayed to target the 3CL protease. Though AG7088 is inactive (IC50 > 100 mu M), the ketomethylene isosteres and tripeptide alpha,beta-unsaturated esters containing both P1 and P2 phenylalanine residues show modest inhibitory activity (IC50 = 11-39 mu M). The Phe-Phe dipeptide inhibitors 18a-e are designed on the basis of computer modeling of the enzyme-inhibitor complex. The most potent inhibitor 18c with an inhibition constant of 0.52 mu M is obtained by condensation of the Phe-Phe dipeptide alpha,beta-unsaturated ester with 4-(dimethylamino)cinnamic acid. The cell-based assays also indicate that 18c is a nontoxic anti-SARS agent with an EC50 value of 0.18 mu M. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.05.065
• 作为产物：
  描述：

  trans-(1'R,2'R)-6-methylhept-4-enoic acid (2'-hydroxy-1'-methyl-2-phenylethyl)methyl amide 在 palladium on activated charcoal lithium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 sodium azide 、 四丙基高钌酸铵 、 4 A molecular sieve 、 氢气 、 溶剂黄146 、 N-甲基吗啉氧化物 、 lithium chloride 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 88.5h， 生成 (alphaR)-alpha-[(3S)-3-(叔-丁基氧羰基氨基)-4-甲基-2-氧代戊基]-4-氟-苯丙酸
  参考文献：
  名称：

  基于结构的设计，合成和不可逆转的人类鼻病毒3C蛋白酶抑制剂的生物学评估。3.含酮亚甲基拟肽的结构活性研究。

  摘要：

  描述了各种含酮亚甲基的人鼻病毒（HRV）3C蛋白酶（3CP）抑制剂的基于结构的设计，化学合成和生物学评估。这些化合物由拟肽结合决定簇和丙酸乙酯迈克尔受体部分组成，其与3C酶的活性位点半胱氨酸残基形成不可逆的共价加合物。相对于相应的肽衍生的分子，含酮亚甲基的抑制剂通常显示出略微降低的3CP抑制活性，但它们也显示出显着改善的抗病毒特性。已显示对含酮亚甲基化合物的优化可提供几种高活性3C蛋白酶抑制剂，它们可作为有效的抗鼻病毒药物（EC90 = <1 microM），对抗细胞培养中的多种病毒血清型。

  DOI：

  10.1021/jm980537b

文献信息

• Improved synthesis of rupintrivir
  作者：DaiZong Lin、WangKe Qian、Rolf Hilgenfeld、HuaLiang Jiang、KaiXian Chen、Hong Liu

  DOI：10.1007/s11426-011-4478-5

  日期：2012.6

  An improved synthesis of rupintrivir (AG7088) was accomplished using three amino acids (l-glutamic acid, d-4-fluorophenylalanine, and l-valine) as the building blocks. The key fragment ketomethylene dipeptide isostere was constructed with the valine derivative and phenylpropionic acid derivative, followed by coupling with a lactam derivative and an isoxazole acid chloride to provide AG7088 totally in eight steps.

  对rupintrivir (AG7088) 的改进合成使用了三种氨基酸（l-谷氨酸、d-4-氟苯丙氨酸和l-缬氨酸）作为构建块。关键片段酮亚甲基二肽异构体通过缬氨酸衍生物和苯丙酸衍生物的构建而成，随后与内酰胺衍生物和异恶唑酸氯化物偶联，最终在八个步骤中合成出AG7088。
• An efficient and tunable route to AG7088, a rhinovirus protease inhibitor
  作者：Dawei Ma、Weiqing Xie、Bin Zou、Qiong Lei、Duanqing Pei

  DOI：10.1016/j.tetlet.2004.08.179

  日期：2004.10

  Aldol reaction of N,N-dibenzyl valinal with propiolic acid ethyl ester derived lithium reagent provides anti-aminoalcohol 8 and syn-aminoalcohol 9, which are converted into the lactone 6 via two different routes. Alkylation of 6 followed by lactone ring opening afford the acid 2a, which is coupled with the amine 3 and 5-methylisoxazole-3-carboxylate acid 1, respectively, to deliver AG7088.

  N，N-二苄基缬氨酸与丙酸乙酯衍生的锂试剂的醛醇缩合反应得到抗氨基醇8和顺氨基醇9，它们通过两种不同的途径转化为内酯6。6的烷基化，然后内酯开环，得到酸2a，其与胺3和5-甲基异恶唑-3-羧酸酯1分别偶联，以递送AG7088。
• Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 4. Incorporation of P₁ Lactam Moieties as <scp>l</scp>-Glutamine Replacements
  作者：Peter S. Dragovich、Thomas J. Prins、Ru Zhou、Stephen E. Webber、Joseph T. Marakovits、Shella A. Fuhrman、Amy K. Patick、David A. Matthews、Caroline A. Lee、Clifford E. Ford、Benjamin J. Burke、Paul A. Rejto、Thomas F. Hendrickson、Tove Tuntland、Edward L. Brown、James W. Meador、Rose Ann Ferre、James E. V. Harr、Maha B. Kosa、Stephen T. Worland

  DOI：10.1021/jm9805384

  日期：1999.4.1

  The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P-1 lactam moieties in lieu of an L-glutamine residue are described. These compounds are comprised of a tripeptidyl or peptidomimetic binding determinant and an ethyl propenoate Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The P-1-lactam-containing inhibitors display significantly increased 3CP inhibition activity along with improved antirhinoviral properties relative to corresponding L-glutamine-derived molecules. In addition, several lactam-containing compounds exhibit excellent selectivity for HRV 3CP over several other serine and cysteine proteases and are not appreciably degraded by a variety of biological agents. One of the most potent inhibitors (AG7088, mean antirhinoviral EC90 0.10 approximate to mu M, n = 46 serotypes) is shown to warrant additional preclinical development to explore its potential for use as an antirhinoviral agent.