论文部分内容阅读
目的:合成并研究DPP4抑制剂阿格列汀衍生物的降糖活性。方法:根据DPP-Ⅳ抑制剂药物阿格列汀,采用骨架跃迁的策略,将嘧啶二酮骨架跃迁为稠合杂环结构吡咯并[1,2-f][1,2,4]三嗪,经过结构优化设计并合成了8个含吡咯并[1,2-f][1,2,4]三嗪结构的新化合物,并通过~1H-NMR和LC-MS确定了它们的结构。对所有化合物进行了体外和体内等药理活性实验,研究了它们的降糖活性。结果:与对照药alogliptin(IC_(50)=8.47nmol·L~(-1))相比,除化合物12a,12d的DPP-Ⅳ体外抑制活性(IC_(50)9nmol·L~(-1))稍弱外,其余化合物的活性均较好,而化合物12e,12f,12g,12h的活性(IC_(50)<4nmol·L~(-1))是alogliptin的2~3.5倍。体内等药理实验显示化合物12h的药动学参数较好,具有很强的降血糖作用。结论:化合物12h具有较好的降糖活性,适合进一步对12h进行其他临床前实验。
AIM: To synthesize and study the hypoglycemic activity of the alogliptin derivative, a DPP4 inhibitor. Methods: According to the strategy of the framework transition of DPP-IV inhibitor alogliptin, the framework of pyrimidinedione was changed to pyrrolo [1,2-f] [1,2,4] triazine , Eight new compounds with pyrrolo [1,2-f] [1,2,4] triazine structure were designed and synthesized by structural optimization. Their structures were confirmed by ~ 1H-NMR and LC-MS. All compounds were in vitro and in vivo pharmacological activity experiments to study their hypoglycemic activity. RESULTS: Compared with the control drug alogliptin (IC 50 = 8.47 nmol·L -1), DPP-Ⅳ inhibited the activity of IC50 (50 nmol·L -1) ), While the activity of other compounds was better, while the activity of compounds 12e, 12f, 12g and 12h (IC 50 (4nmol·L -1)) was 2 ~ 3.5 times higher than that of alogliptin. In vivo and other pharmacological experiments show that the compound 12h pharmacokinetic parameters are good, with a strong hypoglycemic effect. Conclusion: Compound 12h has good hypoglycemic activity and is suitable for further preclinical experiments at 12h.