(3S)-3-氨基-1-羟基-3,4-二氢喹啉-2-酮盐酸盐 | 177943-33-8

• 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
• 中文名称: (3S)-3-氨基-1-羟基-3,4-二氢喹啉-2-酮盐酸盐
• 中文别名: L-3-氨基3,4-二氢-1-羟基咔唑盐酸盐；PF-04859989盐酸盐；PF-4859989盐酸盐；PF04859989盐酸盐；（3S）-3-氨基-1-羟基-3,4-二氢喹啉-2（1H）-酮；L-3-氨基3,4-二氢-1-羟基咔唑盐酸盐；PF-4859989盐酸盐,PF04859989盐酸盐,（3S）-3-氨基-1-羟基-3,4-二氢喹啉-2（1H）-酮
• 英文名称: (3S)-3-amino-1-hydroxy-3,4-dihydroquinolin-2(1H)-one hydrochloride
• 英文别名: (S)-3-Amino-1-hydroxy-3,4-dihydroquinolin-2(1H)-one hydrochloride；(3S)-3-amino-1-hydroxy-3,4-dihydroquinolin-2-one;hydrochloride
• CAS: 177943-33-8
• 化学式: C₉H₁₀N₂O₂*ClH
• 分子量: 214.652
• InChiKey: WZOBDOKCHIUXAY-FJXQXJEOSA-N

物化性质

• 溶解度：
  在水中的溶解度为20mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  0.71
• 重原子数：
  14
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  66.6
• 氢给体数：
  3
• 氢受体数：
  3

安全信息

• WGK Germany：
  3
• 海关编码：
  2933790090

制备方法与用途

生物活性

PF-04859989 氢氯化物是一种可透过血脑屏障的、不可逆的犬尿氨酸转氨酶 KAT II 抑制剂。它对 hKAT Ⅱ 和 rKAT Ⅱ 的 IC50 值分别为 23 nM 和 263 nM。PF-04859989 氢氯化物对 KAT Ⅱ 的选择性高于人 KAT Ⅰ、KAT Ⅲ 和 KAT Ⅳ（IC50 分别为 22 μM、11 μM 和 >50 μM）。

体内研究

在大鼠的体内药代动力学和疗效研究中，显示 PF-04859989 是一种透过血脑屏障且不可逆抑制 KAT Ⅱ 的药物。给大鼠注射 10 mg/kg（腹腔注射）后，其大脑中的 kynurenic 酸水平降低了约 50%。接受 5 mg/kg （静脉注射）PF-04859989 大鼠的自发活跃多巴胺（DA）神经元数量显著减少。

研究结果：

• 动物模型：雄性 Sprague-Dawley 大鼠
• 剂量：5 mg/kg
• 给药方式：静脉注射
• 结果：与对照组相比，表现出自发活跃的多巴胺（DA）神经元数量显著减少。

反应信息

• 作为产物：
  描述：

  2-nitro-L-phenylalanine 在 platinum on carbon 、 氢气 、 盐酸 作用下， 以 吡啶 、 甲醇 为溶剂， 10.0~20.0 ℃ 、206.85 kPa 条件下， 反应 50.5h， 以70%的产率得到(3S)-3-氨基-1-羟基-3,4-二氢喹啉-2-酮盐酸盐
  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

• [EN] CARBOSTYRIL DERIVATIVES AS MATRIX METALLOPROTEINASES INHIBITORS<br/>[FR] DERIVES DE CARBOSTYRILE EMPLOYES COMME INHIBITEURS DE METALLOPROTEINASES DE LA MATRICE EXTRACELLULAIRE
  申请人：OTSUKA PHARMACEUTICAL CO., LTD.

  公开号：WO1994021612A1

  公开（公告）日：1994-09-29

  (EN) This invention provides a carbostyril derivative of formula (1), where R1, R2, R3, R4, R5, R6 and n are as defined, or its salt. This carbostyril derivative or its salt possess an excellent matrix metalloproteinases inhibitory action.(FR) Dérivé de carbostyrile de la formule (1), dans laquelle R1, R2, R3, R4, R5, R6 et n sont tels que définis, ou son sel. Ce dérivé de carbostyrile ou son sel possède d'excellentes propriétés de neutralisation des métalloprotéinases de la matrice extracellulaire.

  该发明提供了一种式为（1）的羧基苯基咔唑衍生物，其中R1、R2、R3、R4、R5、R6和n如定义所述，或其盐。该羧基苯基咔唑衍生物或其盐具有出色的基质金属蛋白酶抑制作用。
• CARBOSTYRIL DERIVATIVES AS MATRIX METALLOPROTEINASES INHIBITORS
  申请人：OTSUKA PHARMACEUTICAL CO., LTD.

  公开号：EP0641323A1

  公开（公告）日：1995-03-08
• US5594006A
  申请人：——

  公开号：US5594006A

  公开（公告）日：1997-01-14
• 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.