(alphaR)-4-氟-alpha-[(3S)-4-甲基-3-[[(5-甲基-3-异恶唑基)羰基]氨基]-2-氧代戊基]-苯丙酸 | 328086-55-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 中文名称: (alphaR)-4-氟-alpha-[(3S)-4-甲基-3-[[(5-甲基-3-异恶唑基)羰基]氨基]-2-氧代戊基]-苯丙酸
• 英文名称: (2R,5S)-2-[(4-fluorophenyl)methyl]-6-methyl-5-[(5-methyl-1,2-oxazole-3-carbonyl)amino]-4-oxoheptanoic acid
• CAS: 328086-55-1
• 化学式: C₂₀H₂₃FN₂O₅
• 分子量: 390.411
• InChiKey: JFQOJCVRJLLFGZ-KDOFPFPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (alphaR)-4-氟-alpha-[(3S)-4-甲基-3-[[(5-甲基-3-异恶唑基)羰基]氨基]-2-氧代戊基]-苯丙酸 、 在 N,N-二异丙基乙胺 、 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 为溶剂， 生成 N-((3S,6R)-6-(4-fluorobenzyl)-2-methyl-7-(((S,E)-4-(methylsulfonyl)-1-((S)-2-oxopyrrolidin-3-yl)but-3-en-2-yl)amino)-4,7-dioxoheptan-3-yl)-5-methylisoxazole-3-carboxamide
  参考文献：
  名称：

  抗EV71药物的设计，合成和生物学评估

  摘要：

  肠病毒71（EV71）是手足口病（HFMD）的主要病原体，可将其感染传播到中枢神经系统和其他系统，造成严重后果。在本文中，描述了结合了迈克尔受体的各种抗EV71药物的设计，化学合成和生物学评估。进一步的SAR研究表明，内酯类型的Michael受体在基于细胞的测定中提供了具有高抗EV71活性的抗EV71候选药物的新线索，并增强了小鼠血浆的稳定性。最有效的化合物之一（2K，基于细胞的抗EV71 EC 50  = 0.028μM）显示出对小鼠血浆的可接受的稳定性，从而通过IP给药在小鼠体内产生了有希望的药代动力学。

  DOI：

  10.1016/j.bmcl.2016.05.036
• 作为产物：
  描述：

  CBZ-L-缬氨酸 在 palladium on activated charcoal 、 四(三苯基膦)钯 吗啉 、 N-甲基吗啉 、 盐酸 、 lithium hydroxide 、 氢气 、 sodium hydride 、 caesium carbonate 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 75.5h， 生成 (alphaR)-4-氟-alpha-[(3S)-4-甲基-3-[[(5-甲基-3-异恶唑基)羰基]氨基]-2-氧代戊基]-苯丙酸
  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

文献信息

• Chemoenzymatic synthesis of ketomethylene tripeptide isosteres
  作者：Junhua Tao、Shanghui Hu、Qingping Tian、Naresh Nayyar、Srin Babu

  DOI：10.1016/j.tetasy.2004.11.092

  日期：2005.2

  A chemoenzymatic method is described for the synthesis of a desired ketomethylene tripeptide isostere. The key step is an enzymatic hydrolysis, which removes the C-terminal ester-protecting group under mild conditions without epimerizing the existing stereogenic center and produces the desired stereoisomer in high enantiomeric excess (98% de, 97% ee). The method is short with overall 15-20% yields after seven synthetic steps from readily available starting materials being obtained. (C) 2005 Published by Elsevier Ltd.
• Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters
  作者：Jiun-Jie Shie、Jim-Min Fang、Tun-Hsun Kuo、Chih-Jung Kuo、Po-Huang Liang、Hung-Jyun Huang、Yin-Ta Wu、Jia-Tsrong Jan、Yih-Shyun E. Cheng、Chi-Huey Wong

  DOI：10.1016/j.bmc.2005.05.065

  日期：2005.9

  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.
• Design, synthesis, and biological evaluation of anti-EV71 agents
  作者：Peng Li、Bailing Yang、Fei Hao、Ping Wang、Haiying He、Lei Huang、Xuan Zhang、Shengbin Zhang、Xuanjia Peng、Ke Yin、Jiao Hu、Xinsheng Chen、Zhengxian Gu、Li Wang、Liang Shen、Guoping Hu、Ning Li、Jian Li、Shuhui Chen、Wei Xiao、Zhenzhong Wang、Qingming Guo、Xiujuan Chang、Lanjun Zhang、Qixu Cai、Tianwei Lin

  DOI：10.1016/j.bmcl.2016.05.036

  日期：2016.7

  Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), which can spread its infections to the central nervous and other systems with severe consequences. In this article, design, chemical synthesis, and biological evaluation of various anti-EV71 agents which incorporate Michael acceptors are described. Further SAR study demonstrated that lactone type of Michael acceptor

  肠病毒71（EV71）是手足口病（HFMD）的主要病原体，可将其感染传播到中枢神经系统和其他系统，造成严重后果。在本文中，描述了结合了迈克尔受体的各种抗EV71药物的设计，化学合成和生物学评估。进一步的SAR研究表明，内酯类型的Michael受体在基于细胞的测定中提供了具有高抗EV71活性的抗EV71候选药物的新线索，并增强了小鼠血浆的稳定性。最有效的化合物之一（2K，基于细胞的抗EV71 EC 50  = 0.028μM）显示出对小鼠血浆的可接受的稳定性，从而通过IP给药在小鼠体内产生了有希望的药代动力学。