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.
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 by1 H NMR,13 C 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.
出处
《高等学校化学学报》
SCIE
EI
CAS
CSCD
北大核心
2017年第10期1778-1787,共10页
Chemical Journal of Chinese Universities
基金
江苏省产学研前瞻性联合研究项目(批准号:BY2015072-02)资助~~
关键词
绿卡色林
前药
代谢稳定
体内活性
Lorcaserin
Prodrug
Metabolic stability
Biological activity in vivo
