高等学校化学学报 ›› 2017, Vol. 38 ›› Issue (10): 1778.doi: 10.7503/cjcu20170094

• 有机化学 • 上一篇    下一篇

绿卡色林衍生物的合成、 体外代谢及体内活性研究

张灵芝1, 蒋敏瑞2, 魏萍3, 朱启华1(), 龚国清2, 卞学国3, 徐云根1()   

  1. 1. 中国药科大学药物化学系, 2. 药理系, 南京 210009
    3. 南京医工医药技术有限公司, 南京 210009
  • 收稿日期:2017-02-18 出版日期:2017-10-10 发布日期:2017-09-22
  • 作者简介:联系人简介: 朱启华, 男, 博士, 副教授, 主要从事新药分子的设计与合成研究. E-mail:zhuqihua@vip.126.com;徐云根, 男, 博士, 教授, 博士生导师, 主要从事新药分子的设计与合成及药物合成新工艺研究. E-mail:xyg@cpu.edu.cn
  • 基金资助:
    江苏省产学研前瞻性联合研究项目(批准号: BY2015072-02)资助

Synthesis, Metabolic Stability and Biological Activity in vivo of Lorcaserin Derivatives

ZHANG Lingzhi1, JIANG Minrui2, WEI Ping3, ZHU Qihua1,*(), GONG Guoqing2, BIAN Xueguo3, XU Yungen1,*()   

  1. 1. Department of Medicinal Chemistry, 2.Department of Pharmacology,China Pharmaceutical University, Nanjing 210009, China
    3.Nanjing Industrial Pharmaceutical Institute Co., Ltd., Nanjing 210009, China
  • Received:2017-02-18 Online:2017-10-10 Published:2017-09-22
  • Contact: ZHU Qihua,XU Yungen E-mail:zhuqihua@vip.126.com;xyg@cpu.edu.cn
  • Supported by:
    † Supported by the Research and Production of Prospective Joint Research Project of Jiangsu Province, China(No.BY2015072-02).

摘要:

将选择性5-HT2C受体激动剂类减肥药绿卡色林分子中的仲胺转化成氨基甲酸酯类前药, 设计合成了13个氨基甲酸酯类化合物. 新化合物的结构经核磁共振波谱、 红外光谱及高分辨质谱确证. 通过体外代谢稳定性实验, 筛选出半衰期长且可通过代谢持续产生绿卡色林的新化合物6b. 对化合物6b的大鼠减肥药理实验结果表明, 在日剂量相同的条件下, 化合物6b给药1次/d比绿卡色林给药2次/d的减肥效果略好.

关键词: 绿卡色林, 前药, 代谢稳定, 体内活性

Abstract:

To improve oral bioavailability and metabolic stability while maintaining the activity and selectivity, 13 carbamate prodrugs of lorcaserin were designed and synthesized by the structural modification of the secondary amine group. The structure of target compounds were confirmed by 1H NMR, 13C NMR, HRMS and IR. In vitro metabolic stabilities of 13 target compounds were explored by rat liver microsomes incubation experiment, among which compound 6b showed a longer half-life and can generate lorcaserin continuously by metabolism. In high-fat diet rats model, compound 6b exhibited slightly better weight loss effect than lorcaserin at the equimolar daily doses.

Key words: Lorcaserin, Prodrug, Metabolic stability, Biological activity in vivo

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