ethyl-3-<(5'-methylisoxazole-3'-carbonyl)-L-Val-L-Phe(4-F)-L-<(N-2,4-dimethoxybenzyl)-(S)-Pyrrol-Ala>>-E-propenoate | 223526-65-6

• 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: ethyl-3-<(5'-methylisoxazole-3'-carbonyl)-L-Val-L-Phe(4-F)-L-<(N-2,4-dimethoxybenzyl)-(S)-Pyrrol-Ala>>-E-propenoate
• 英文别名: ethyl (E,4S)-5-[(3S)-1-[(2,4-dimethoxyphenyl)methyl]-2-oxopyrrolidin-3-yl]-4-[[(2S)-3-(4-fluorophenyl)-2-[[(2S)-3-methyl-2-[(5-methyl-1,2-oxazole-3-carbonyl)amino]butanoyl]amino]propanoyl]amino]pent-2-enoate
• CAS: 223526-65-6
• 化学式: C₃₉H₄₈FN₅O₉
• 分子量: 749.837
• InChiKey: HJPSQABFSHXUHQ-IZOIKKLJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  54
• 可旋转键数：
  19
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  178
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  ethyl-3-<(5'-methylisoxazole-3'-carbonyl)-L-Val-L-Phe(4-F)-L-<(N-2,4-dimethoxybenzyl)-(S)-Pyrrol-Ala>>-E-propenoate 在 水 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 氯仿 为溶剂， 反应 9.0h， 以56%的产率得到ethyl (E,4S)-4-[[(2S)-3-(4-fluorophenyl)-2-[[(2S)-3-methyl-2-[(5-methylisoxazole-3-carbonyl)amino]butanoyl]amino]propanoyl]amino]-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 4. Incorporation of P₁ Lactam Moieties as l-Glutamine Replacements

  摘要：

  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.

  DOI：

  10.1021/jm9805384
• 作为产物：
  描述：

  (4S)-4-(2'-carboxyethyl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester 在 N-甲基吗啉 、 盐酸 、 甲醇 、 草酰氯 、 二甲基硫 、 sodium acetate 、 sodium hexamethyldisilazane 、 三甲基乙酰氯 、 sodium cyanoborohydride 、 对甲苯磺酸 、 臭氧 、 二甲基亚砜 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 lithium chloride 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 64.75h， 生成 ethyl-3-<(5'-methylisoxazole-3'-carbonyl)-L-Val-L-Phe(4-F)-L-<(N-2,4-dimethoxybenzyl)-(S)-Pyrrol-Ala>>-E-propenoate
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 4. Incorporation of P₁ Lactam Moieties as l-Glutamine Replacements

  摘要：

  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.

  DOI：

  10.1021/jm9805384

文献信息

• 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.