(3S,3aR,6aS)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methylhexahydropyrrolo[3,2-b]pyrrol-2-one | 214337-25-4

• 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-methylhexahydropyrrolo[3,2-b]pyrrol-2-one
• 英文别名: (3aS,6S,6aR)-1-[(2S)-1-[5-(dimethylamino)naphthalen-1-yl]sulfonylpyrrolidine-2-carbonyl]-6-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one
• CAS: 214337-25-4
• 化学式: C₂₄H₃₀N₄O₄S
• 分子量: 470.593
• InChiKey: YIGOEFHWIMSIGS-DKWQAAHISA-N

物化性质

• 密度：
  1.333±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  98.4
• 氢给体数：
  1
• 氢受体数：
  6

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-methylhexahydropyrrolo[3,2-b]pyrrol-2-one 、 cyclopropane carboxylic acid pivalic anhydride 在 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 (3S,3aR,6aS)-1-(cyclopropylcarbonyl)-4-[((2S)-1-{[5-(dimethylamino)-1-naphthyl]sulfonyl}pyrrolidin-2-yl)carbonyl]-3-methylhexahydropyrrolo[3,2-b]pyrrol-2(1H)-one
  参考文献：
  名称：

  Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3: potency and plasma stability

  摘要：

  Mechanism-based inhibitors of HCMV protease, which Lire stable to human plasma (greater than or equal to20h) and have single-figure potency in the muM range against HCMV protease, have been developed based on the dansylprohne alpha-methyl pyrrolidine-5,5-translactam nucleus. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00294-9
• 作为产物：
  描述：

  (+/-)-(3S,3aR,6aS)-3-methyl-2-oxohexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester hydrochloride 在 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 (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

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.
• Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3: potency and plasma stability
  作者：Alan D Borthwick、Anne M Exall、Terry M Haley、Deborah L Jackson、Andrew M Mason、Gordon G Weingarten

  DOI：10.1016/s0960-894x(02)00294-9

  日期：2002.7

  Mechanism-based inhibitors of HCMV protease, which Lire stable to human plasma (greater than or equal to20h) and have single-figure potency in the muM range against HCMV protease, have been developed based on the dansylprohne alpha-methyl pyrrolidine-5,5-translactam nucleus. (C) 2002 Elsevier Science Ltd. All rights reserved.