N¹-((1S)-3-chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-4-methyl-N²-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-leucinamide

• 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: N¹-((1S)-3-chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-4-methyl-N²-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-leucinamide
• 英文别名: (2R)-N-[(2S)-1-[[(2S)-4-chloro-3-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]amino]-4,4-dimethyl-1-oxopentan-2-yl]oxolane-2-carboxamide
• 化学式: C₂₀H₃₂ClN₃O₅
• 分子量: 429.944
• InChiKey: AMHZATNCWFUDEN-RZLSGREXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N¹-((1S)-3-chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-4-methyl-N²-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-leucinamide 在 potassium carbonate 、 cesium fluoride 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 N¹-((1S)-3-hydroxy-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-4-methyl-N²-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-leucinamide
  参考文献：
  名称：

  Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

  摘要：

  The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL(pro)) in a post-translational processing step that is critical for coronavirus replication. The 3CL(pro) sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL(pro) employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CL(pro) with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.

  DOI：

  10.1021/acs.jmedchem.0c01063
• 作为产物：
  描述：

  (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid 在 N-甲基吗啉 、 盐酸 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醚 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 N¹-((1S)-3-chloro-2-oxo-1-{[(3S)-2-oxopyrrolidin-3-yl]methyl}propyl)-4-methyl-N²-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-leucinamide
  参考文献：
  名称：

  Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19

  摘要：

  The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL(pro)) in a post-translational processing step that is critical for coronavirus replication. The 3CL(pro) sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL(pro) employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CL(pro) with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.

  DOI：

  10.1021/acs.jmedchem.0c01063

文献信息

• [EN] ANTICORONVIRAL COMPOUNDS AND COMPOSITIONS, THEIR PHARMACEUTICAL USES AND MATERIALS FOR THEIR SYNTHESIS<br/>[FR] COMPOSES ET COMPOSITIONS ANTI-CORONAVIRUS, UTILISATIONS PHARMACEUTIQUES ASSOCIEES ET MATERIAUX POUR LA SYNTHESE DE CES COMPOSES ET COMPOSITIONS
  申请人：PFIZER

  公开号：WO2005113580A1

  公开（公告）日：2005-12-01

  The invention relates to methods of inhibiting SARS-related coronavirus viral replication activity comprising contacting a SARS-related coronavirus protease with a therapeutically effective amount of a SARS 3C like protease inhibitor of formula (I), and compositions comprising the same.

  本发明涉及一种抑制SARS相关冠状病毒病毒复制活性的方法，包括将SARS相关冠状病毒蛋白酶与公式（I）的治疗有效量的SARS 3C类蛋白酶抑制剂接触，并且包括相应的组合物。