tert-butyl (3S,4S)-1-(benzyloxy)-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate | 1258544-66-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: tert-butyl (3S,4S)-1-(benzyloxy)-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate
• 英文别名: tert-butyl N-[(3S,4S)-4-methyl-2-oxo-1-phenylmethoxy-3,4-dihydroquinolin-3-yl]carbamate
• CAS: 1258544-66-9
• 化学式: C₂₂H₂₆N₂O₄
• 分子量: 382.459
• InChiKey: VJVVFZOEBVYYGQ-KXBFYZLASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (3S,4S)-1-(benzyloxy)-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate 在 三氟化硼乙醚 、 palladium(II) hydroxide 作用下， 以 四氢呋喃 、 1-甲基-1,4-环己二烯 、 乙醇 为溶剂， 反应 4.0h， 生成 (3S,4S)-3-amino-1-hydroxy-4-methyl-3,4-dihydroquinolin-2(1H)-one
  参考文献：
  名称：

  Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

  摘要：

  Kynurenine aminotransferase (KAT) 11 has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT H. An X-ray crystal structure and C-13 NMR studies of PF-04859989 bound to KAT H have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

  DOI：

  10.1021/ml200204m
• 作为产物：
  描述：

  (2S,3S)-2-((叔-丁氧羰基)氨基)-3-苯基丁酸 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 [双(三氟乙酰氧基)碘]苯 作用下， 以 二氯甲烷 为溶剂， 反应 48.0h， 生成 tert-butyl (3S,4S)-1-(benzyloxy)-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate
  参考文献：
  名称：

  Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia

  摘要：

  Kynurenine aminotransferase (KAT) 11 has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT H. An X-ray crystal structure and C-13 NMR studies of PF-04859989 bound to KAT H have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.

  DOI：

  10.1021/ml200204m

文献信息

• Bicyclic And Tricyclic Compounds As KAT II Inhibitors
  申请人：Claffey Michelle M.

  公开号：US20100324043A1

  公开（公告）日：2010-12-23

  Compounds of Formula X: wherein A, X, Y, Z, R 5 , R 6a , and R 6b are as defined herein, and pharmaceutically acceptable salts thereof, are described as useful for the treatment of cognitive deficits associated with schizophrenia and other neurodegenerative and/or neurological disorders in mammals, including humans.

  化合物X的结构如下：其中A、X、Y、Z、R5、R6a和R6b的定义如本文所述，并且其药用盐被描述为用于治疗与精神分裂症及其他哺乳动物，包括人类，相关的认知缺陷的化合物，以及其他神经退行性和/或神经系统疾病。
• Bicyclic and tricyclic compounds as KAT II inhibitors
  申请人：Pfizer Inc.

  公开号：US08183238B2

  公开（公告）日：2012-05-22

  Compounds of Formula X: wherein A, X, Y, Z, R5, R6a, and R6b are as defined herein, and pharmaceutically acceptable salts thereof, are described as useful for the treatment of cognitive deficits associated with schizophrenia and other neurodegenerative and/or neurological disorders in mammals, including humans.

  化合物X的公式：其中A、X、Y、Z、R5、R6a和R6b的定义如本文所述，并且其药学上可接受的盐，被描述为用于治疗哺乳动物，包括人类，中与精神分裂症和其他神经退行性和/或神经性疾病相关的认知缺陷有关的有用化合物。
• US8183238B2
  申请人：——

  公开号：US8183238B2

  公开（公告）日：2012-05-22
• Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia
  作者：Amy B. Dounay、Marie Anderson、Bruce M. Bechle、Brian M. Campbell、Michelle M. Claffey、Artem Evdokimov、Edelweiss Evrard、Kari R. Fonseca、Xinmin Gan、Somraj Ghosh、Matthew M. Hayward、Weldon Horner、Ji-Young Kim、Laura A. McAllister、Jayvardhan Pandit、Vanessa Paradis、Vinod D. Parikh、Matthew R. Reese、SuoBao Rong、Michelle A. Salafia、Katherine Schuyten、Christine A. Strick、Jamison B. Tuttle、James Valentine、Hong Wang、Laura E. Zawadzke、Patrick R. Verhoest

  DOI：10.1021/ml200204m

  日期：2012.3.8

  Kynurenine aminotransferase (KAT) 11 has been identified as a potential new target for the treatment of cognitive impairment associated with schizophrenia and other psychiatric disorders. Following a high-throughput screen, cyclic hydroxamic acid PF-04859989 was identified as a potent and selective inhibitor of human and rat KAT H. An X-ray crystal structure and C-13 NMR studies of PF-04859989 bound to KAT H have demonstrated that this compound forms a covalent adduct with the enzyme cofactor, pyridoxal phosphate (PLP), in the active site. In vivo pharmacokinetic and efficacy studies in rat show that PF-04859989 is a brain-penetrant, irreversible inhibitor and is capable of reducing brain kynurenic acid by 50% at a dose of 10 mg/kg (sc). Preliminary structure-activity relationship investigations have been completed and have identified the positions on this scaffold best suited to modification for further optimization of this novel series of KAT II inhibitors.