(E)-(S)-4-((S)-2-{3-[(5-methylisoxazole-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}pent-4-ynoylamino)-5-((S)-2-oxopyrrolidin-3-yl)pent-2-enoic acid ethyl ester | 343565-99-1

• 物质功能分类: 原料药
• 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: (E)-(S)-4-((S)-2-{3-[(5-methylisoxazole-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}pent-4-ynoylamino)-5-((S)-2-oxopyrrolidin-3-yl)pent-2-enoic acid ethyl ester
• 英文别名: AG-7404；ethyl (E,4S)-4-[[(2S)-2-[3-[(5-methyl-1,2-oxazole-3-carbonyl)amino]-2-oxopyridin-1-yl]pent-4-ynoyl]amino]-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate
• CAS: 343565-99-1
• 化学式: C₂₆H₂₉N₅O₇
• 分子量: 523.546
• InChiKey: QCUZOJBYWQPLIN-BNMFZAHFSA-N

物化性质

• 沸点：
  924.2±65.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO:0.0(最大浓度 mg/mL);0.0(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  160
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (R)-2-trifluoromethanesulfonyloxypent-4-ynoic acid methyl ester 在 吡啶 、 sodium hydride 、 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 、 N,N-二异丙基乙胺 、 lithium iodide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 25.5h， 生成 (E)-(S)-4-((S)-2-{3-[(5-methylisoxazole-3-carbonyl)amino]-2-oxo-2H-pyridin-1-yl}pent-4-ynoylamino)-5-((S)-2-oxopyrrolidin-3-yl)pent-2-enoic acid ethyl ester
  参考文献：
  名称：

  Structure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors. 8. Pharmacological Optimization of Orally Bioavailable 2-Pyridone-Containing Peptidomimetics

  摘要：

  The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P-2 substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl. P-2 moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[1] 170 000-223 000 M-1 s(-1)), antiviral activity (EC50 = 0.047-0.058 muM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 muM; 7 h CM-monkey plasma levels = 0.057-0.896 muM).

  DOI：

  10.1021/jm030166l

文献信息

• Composition and combined medication method for treating enterovirus infection
  申请人：Institut Pasteur of Shanghai, Chinese Academy of Sciences

  公开号：US10864210B2

  公开（公告）日：2020-12-15

  The present invention provides a composition and a combined medication method for treating an enterovirus infection. In particular, the present invention provides a composition for inhibiting enteroviruses, wherein the composition at least contains an inhibitor of a 3D virus protein and an inhibitor of a capsid protein, or a combination of an inhibitor of a 3C protein and an inhibitor of a 3A protein.

  本发明提供了一种治疗肠道病毒感染的组合物和联合用药方法。特别是，本发明提供了一种用于抑制肠道病毒的组合物，其中该组合物至少含有3D病毒蛋白抑制剂和囊膜蛋白抑制剂，或3C蛋白抑制剂和3A蛋白抑制剂的组合。
• COMPOSITION AND COMBINED MEDICATION METHOD FOR TREATING ENTEROVIRUS INFECTION
  申请人：Institut Pasteur of Shanghai, Chinese Academy of Sciences

  公开号：US20190030027A1

  公开（公告）日：2019-01-31

  The present invention provides a composition and a combined medication method for treating an enterovirus infection. In particular, the present invention provides a composition for inhibiting enteroviruses, wherein the composition at least contains an inhibitor of a 3D virus protein and an inhibitor of a capsid protein, or a combination of an inhibitor of a 3C protein and an inhibitor of a 3A protein.