(20S)-21-(tert-butoxycarbonyl)-19,20,22,23-tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile | 440105-72-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (20S)-21-(tert-butoxycarbonyl)-19,20,22,23-tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile
• 英文别名: tert-butyl (5S)-18-cyano-31-oxo-20-oxa-2,6,11,13-tetrazahexacyclo[19.6.2.12,5.115,19.09,13.024,28]hentriaconta-1(27),9,11,15(30),16,18,21(29),22,24(28),25-decaene-6-carboxylate
• CAS: 440105-72-6
• 化学式: C₃₂H₃₁N₅O₄
• 分子量: 549.629
• InChiKey: JSKQNXFNBHJOIH-NDEPHWFRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  41
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  101
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (20S)-21-(tert-butoxycarbonyl)-19,20,22,23-tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 0.25h， 生成 (20S)-19,20,22,23-tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile hydrochloride
  参考文献：
  名称：

  3-Aminopyrrolidinone Farnesyltransferase Inhibitors:  Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

  摘要：

  A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

  DOI：

  10.1021/jm010531d
• 作为产物：
  描述：

  2-氟-4-甲基苯腈 在 sodium tetrahydroborate 、 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 三氟甲磺酸酐 、 四丁基氟化铵 、 caesium carbonate 、 silver nitrate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 四氯化碳 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 66.67h， 生成 (20S)-21-(tert-butoxycarbonyl)-19,20,22,23-tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile
  参考文献：
  名称：

  3-Aminopyrrolidinone Farnesyltransferase Inhibitors:  Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency

  摘要：

  A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

  DOI：

  10.1021/jm010531d

文献信息

• 3-Aminopyrrolidinone Farnesyltransferase Inhibitors:  Design of Macrocyclic Compounds with Improved Pharmacokinetics and Excellent Cell Potency
  作者：Ian M. Bell、Steven N. Gallicchio、Marc Abrams、Lorena S. Beese、Douglas C. Beshore、Hema Bhimnathwala、Michael J. Bogusky、Carolyn A. Buser、J. Christopher Culberson、Joseph Davide、Michelle Ellis-Hutchings、Christine Fernandes、Jackson B. Gibbs、Samuel L. Graham、Kelly A. Hamilton、George D. Hartman、David C. Heimbrook、Carl F. Homnick、Hans E. Huber、Joel R. Huff、Kelem Kassahun、Kenneth S. Koblan、Nancy E. Kohl、Robert B. Lobell、Joseph J. Lynch,、Ronald Robinson、A. David Rodrigues、Jeffrey S. Taylor、Eileen S. Walsh、Theresa M. Williams、C. Blair Zartman

  DOI：10.1021/jm010531d

  日期：2002.6.1

  A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.