(S)-1-(2-isocyanato-3,3-dimethylbutyl)-4-methylpiperazine-2,6-dione | 1100796-02-8

• 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: (S)-1-(2-isocyanato-3,3-dimethylbutyl)-4-methylpiperazine-2,6-dione
• CAS: 1100796-02-8
• 化学式: C₁₂H₁₉N₃O₃
• 分子量: 253.301
• InChiKey: CHETZRMFPVQHMI-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.04
• 重原子数：
  18.0
• 可旋转键数：
  3.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  70.05
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (S)-1-(2-isocyanato-3,3-dimethylbutyl)-4-methylpiperazine-2,6-dione 、 N-allyl-2-((3S,12S,13S,16aS,17aR,17bS)-13-amino-12,17,17-trimethyl-1,14-dioxohexadecahydro-2H,12H-cyclopropa[3,4]pyrrolo[1,2-e][1]oxa[5,8]diazacyclohexadecin-3-yl)-2-oxoacetamide hydrochloride 在 碳酸氢钠 作用下， 以 二氯甲烷 、 水 、 甲苯 为溶剂， 生成 (16aS,17aR,17bS)-13(S)-[[[[2,2-dimethyl-1(S)-[(4-methyl-2,6-dioxo-1-piperazinyl)methyl]propyl]amino]carbonyl]amino]hexadecahydro-12(S),17,17-trimethyl-α,1,14-trioxo-N-(2-propenyl)-2H,12H-cyclopropa[3,4]pyrrolo[1,2-e][1,5,8]oxadiazacyclohexadecine-3(S)-acetamide
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Oxygen-Containing Macrocyclic Peptidomimetics as Inhibitors of HCV NS3 Protease

  摘要：

  HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, we present the P1-P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential back-up candidates to our first generation drug candidate, Sch 503034 (1). Different P1-P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of L-serine derived macrocycle 32 (K-i* = 3 nM, EC90 = 30 nM) and allo-threonine derived macrocycle 36 (K-i* = 3 nM, EC90 = 30 nM) as potent HCV NS3 protease inhibitors.

  DOI：

  10.1021/jm801201u
• 作为产物：
  描述：

  光气 、 在 碳酸氢钠 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 (S)-1-(2-isocyanato-3,3-dimethylbutyl)-4-methylpiperazine-2,6-dione
  参考文献：
  名称：

  Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease

  摘要：

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

  DOI：

  10.1021/jm801238q

文献信息

• Discovery and Structure−Activity Relationship of P₁−P₃ Ketoamide Derived Macrocyclic Inhibitors of Hepatitis C Virus NS3 Protease
  作者：Srikanth Venkatraman、Francisco Velazquez、Wanli Wu、Melissa Blackman、Kevin X. Chen、Stephane Bogen、Latha Nair、Xiao Tong、Robert Chase、Andrea Hart、Sony Agrawal、John Pichardo、Andrew Prongay、Kuo-Chi Cheng、Viyyoor Girijavallabhan、John Piwinski、Neng-Yang Shih、F. George Njoroge

  DOI：10.1021/jm800940u

  日期：2009.1.22

  Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, and affects more than 200 million people worldwide. Although combination therapy of interferon-alpha and ribavirin is reasonably successful in treating majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of a series of ketoamide derived P-1-P-3 macrocyclic inhibitors that are more potent than the first generation clinical candidate, boceprevir (1, Sch 503034), is discussed. The optimization of these macrocyclic inhibitors identified a P-3 imide capped analogue 52 that was 20 times more potent than 1 and demonstrated good oral pharmacokinetics in rats. X-ray structure of 52 bound to NS3 protease and biological data are also discussed.