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。
• Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19
  作者：Robert L. Hoffman、Robert S. Kania、Mary A. Brothers、Jay F. Davies、Rose A. Ferre、Ketan S. Gajiwala、Mingying He、Robert J. Hogan、Kirk Kozminski、Lilian Y. Li、Jonathan W. Lockner、Jihong Lou、Michelle T. Marra、Lennert J. Mitchell、Brion W. Murray、James A. Nieman、Stephen Noell、Simon P. Planken、Thomas Rowe、Kevin Ryan、George J. Smith、James E. Solowiej、Claire M. Steppan、Barbara Taggart

  DOI：10.1021/acs.jmedchem.0c01063

  日期：2020.11.12

  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.