(R)-2-fluoro-4-(5-{[1-(3-hydroxybenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile | 330213-78-0

• 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: (R)-2-fluoro-4-(5-{[1-(3-hydroxybenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile
• 英文别名: 2-fluoro-4-[[5-[[[(3R)-1-[(3-hydroxyphenyl)methyl]-2-oxopyrrolidin-3-yl]amino]methyl]imidazol-1-yl]methyl]benzonitrile
• CAS: 330213-78-0
• 化学式: C₂₃H₂₂FN₅O₂
• 分子量: 419.458
• InChiKey: LOFWBFIAMRSCRC-JOCHJYFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  94.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-2-fluoro-4-(5-{[1-(3-hydroxybenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以73%的产率得到(6R)-27-oxo-20-oxa-3,7,11,13-tetrazapentacyclo[19.3.1.13,6.115,19.09,13]heptacosa-1(25),9,11,15(26),16,18,21,23-octaene-18-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
• 作为产物：
  描述：

  1-(azidomethyl)-3-(benzyloxy)benzene 在 20percent Pd(OH)2/C 盐酸 、 lithium aluminium tetrahydride 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 氢气 、 sodium cyanoborohydride 、 N,N-二异丙基乙胺 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 75.75h， 生成 (R)-2-fluoro-4-(5-{[1-(3-hydroxybenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile
  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

• Inhibitors of prenyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US06441017B1

  公开（公告）日：2002-08-27

  The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemothera-peutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.

  本发明涉及一种宏环化合物，其抑制戊二烯蛋白转移酶（FTase）和致癌基因蛋白Ras的戊二烯化。本发明还涉及含有本发明化合物的化疗组合物以及抑制戊二烯蛋白转移酶和致癌基因蛋白Ras的方法。
• US6441017B1
  申请人：——

  公开号：US6441017B1

  公开（公告）日：2002-08-27
• 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.