(3S,3aR,6aS)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methyl-2-oxohexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester | 214337-24-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (3S,3aR,6aS)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methyl-2-oxohexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (3aS,6S,6aR)-1-[(2S)-1-[5-(dimethylamino)naphthalen-1-yl]sulfonylpyrrolidine-2-carbonyl]-6-methyl-5-oxo-3,3a,6,6a-tetrahydro-2H-pyrrolo[3,2-b]pyrrole-4-carboxylate
• CAS: 214337-24-3
• 化学式: C₂₉H₃₈N₄O₆S
• 分子量: 570.71
• InChiKey: GOGMOVHYHLIKDT-ZDKQOFBKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  116
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (3S,3aR,6aS)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methyl-2-oxohexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester 在 三氟乙酸 作用下， 反应 0.67h， 以95%的产率得到(3S,3aR,6aS)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methylhexahydropyrrolo[3,2-b]pyrrol-2-one
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxohexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 2. Potency and Chirality

  摘要：

  The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.

  DOI：

  10.1021/jm0102203
• 作为产物：
  描述：

  rel-(3S,3aR,6aS)-3-methyl-2-oxo-hexahydro-pyrrolo[3,2-b]pyrrole-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester 在 10percent Pd/C 盐酸 、 氢气 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 20.33h， 生成 (3S,3aR,6aS)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methyl-2-oxohexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Design and Synthesis of Pyrrolidine-5,5-trans-lactams (5-Oxohexahydropyrrolo[3,2-b]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 2. Potency and Chirality

  摘要：

  The stereospecific synthesis of a series of alpha-methylpyrrolidine-5,5-trans-lactam inhibitors of human cytomegalovirus (HCMV) protease is described. Examination of the SAR in this series has defined the size and chirality of the alpha-substituent, optimized the acyl substituent on the lactam nitrogen, and defined the steric constraint of this functionality. The SAR of the functionality on the pyrrolidine nitrogen of the trans-lactam has been investigated, and this has led to the discovery of potent serine protease inhibitors that are highly selective for the viral enzyme over the mammalian enzymes elastase, thrombin, and acetylcholine esterase. The mechanism of action of our lead compounds has been established by mass spectrometry, and enzymatic degradation of HCMV deltaAla protease acylated with these inhibitors showed that Ser 132 is the active site nucleophile. The crystal structure of HCMV protease was obtained and used to model the conformationally restricted, chiral (S)-proline-alpha-methyl-5,5-trans-lactams into the active site groove of the enzyme, enabling us to direct and rationalize the SAR in this series. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the dansyl-(S)-proline alpha-methyl-5,5-trans-lactam template, which have low nanomolar activity against the viral enzyme.

  DOI：

  10.1021/jm0102203