GC376 | 1416992-39-6

• 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: GC376
• 英文别名: GC-376；sodium;(2S)-1-hydroxy-2-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonate
• CAS: 1416992-39-6
• 化学式: C₂₁H₃₀N₃O₈S*Na
• 分子量: 507.54
• InChiKey: BSPJDKCMFIPBAW-JPBGFCRCSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -2.79
• 重原子数：
  34
• 可旋转键数：
  12
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  182
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (S)-(-)-2-异氰酰基-4-甲基戊酸甲酯 在 锂硼氢 、 水 、 1-羟基苯并三唑 、 戴斯-马丁氧化剂 、 sodium hydrogensulfite 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 GC376
  参考文献：
  名称：

  Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors

  摘要：

  Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and alpha-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as alpha-ketoheterocycles and alpha-ketoesters. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.11.026

文献信息

• Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies
  作者：Anushka C. Galasiti Kankanamalage、Yunjeong Kim、Pathum M. Weerawarna、Roxanne Adeline Z. Uy、Vishnu C. Damalanka、Sivakoteswara Rao Mandadapu、Kevin R. Alliston、Nurjahan Mehzabeen、Kevin P. Battaile、Scott Lovell、Kyeong-Ok Chang、William C. Groutas

  DOI：10.1021/jm5019934

  日期：2015.4.9

  Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.