(+/-)-(3S,3aR,6aS)-1-acetyl-3-methylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

• 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: (+/-)-(3S,3aR,6aS)-1-acetyl-3-methylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride
• 英文别名: (3aS,6S,6aR)-4-acetyl-6-methyl-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-1-ium-5-one;chloride
• 化学式: C₉H₁₄N₂O₂*ClH
• 分子量: 218.683
• InChiKey: QTGAXSGIJHBSQF-IMSVJKHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.28
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.78
• 拓扑面积：
  54
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  苯氧乙酸 、 (+/-)-(3S,3aR,6aS)-1-acetyl-3-methylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 20.33h， 以51%的产率得到(+/-)-(3S,3aR,6aS)-1-acetyl-3-methyl-4-(phenoxyacetyl)-hexahydropyrrolo[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-(3aS,6S,6aR)-4-acetyl-6-methyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester 在 10percent Pd/C 盐酸 、 氢气 作用下， 以 乙醚 、 异丙醇 为溶剂， 反应 3.5h， 以99%的产率得到(+/-)-(3S,3aR,6aS)-1-acetyl-3-methylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride
  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

文献信息

• Design and Synthesis of Pyrrolidine-5,5-<i>trans-</i>lactams (5-Oxohexahydropyrrolo[3,2-<i>b</i>]pyrroles) as Novel Mechanism-Based Inhibitors of Human Cytomegalovirus Protease. 2. Potency and Chirality
  作者：Alan D. Borthwick、Andrew J. Crame、Peter F. Ertl、Anne M. Exall、Terry M. Haley、Graham J. Hart、Andrew M. Mason、Andrew M. K. Pennell、Onkar M. P. Singh、Gordon G. Weingarten、James M. Woolven

  DOI：10.1021/jm0102203

  日期：2002.1.1

  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.