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4-苯氧基喹啉羟甲戊二酸内酯类的合成及抑制HMG CoA还原酶活性研究

蔡正艳*, 潘竞, 郝群, 周伟澄, 张陆勇   

  1. 1. 上海医药工业研究院 创新药物与制药工艺国家重点实验室, 上海 200437
    2. 中国药科大学 新药筛选中心, 江苏 南京 210009
  • 收稿日期:2009-09-29 修回日期:2009-11-15 出版日期:2010-01-15 发布日期:2010-01-15
  • 通讯作者: 蔡正艳*

Synthesis of 4-phenoxy quinoline mevalonolactones and evaluation of their HMG CoA reductase inhibition activities

Zheng-Yan Cai*, Jing Pan, Qun Hao, Wei-Cheng Zhou, Lu-Yong Zhang   

  1. 1. State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China
    2. Screening Center for New Drugs, China Pharmaceutical University, Nanjing 210009, China
  • Received:2009-09-29 Revised:2009-11-15 Online:2010-01-15 Published:2010-01-15
  • Contact: Zheng-Yan Cai*

摘要: 本文合成了一系列4-苯氧基喹啉羟甲戊二酸内酯类衍生物, 测定了其对大鼠3-羟基-3-甲基戊二酰辅酶A还原酶 (HMG CoA还原酶) 的抑制作用, 其中化合物(4R, 6S)-6-{(E)-2-[6-氟-7-氯-4-(4-氟苯氧基-喹啉)-3-基-]-乙烯基}-3,4,5,6-四氢-4-羟基-2H-吡喃-2-酮(3d)显示出优于对照药瑞舒伐他汀或匹伐他汀的体外抑制活性。此化合物已作为潜在的降血脂候选药物进行深入的临床前研究。

关键词: HMG CoA还原酶抑制剂, 4-苯氧基喹啉, 合成

Abstract: A series of 4-phenoxy quinoline-based mevalonolactone derivatives have been synthesized and evaluated as 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) inhibitors. One member of this series, (4R,6S)-6-{(E)-2-[6-fluoro-7-chloro-4-(4-fluorophenoxy-quinoline)-3-yl-]-ethenyl}-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (3d), showed more potent activity than rosuvastatin or pitavastatin to inhibit the rat HMG CoA reductase in vitro. This compound was selected for the extensive preclinical development as a potential hypocholesterolemic candidate.

Key words: HMG CoA reductase inhibitors, 4-Phenoxy quinolines, Synthesis

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Supporting: Foundation items: The State New Drug Innovation (Grant No. 2009ZX09301-007), Shanghai Rising-Star Program (Grant No. 08QB1403800) and Shanghai Innovation Action Project (Grant No. 09431901300).
*Corresponding author. Tel./fax: 86-21-35052484