期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 24, 页码 9955-9968出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm4017448
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资金
- National Natural Science Foundation of China [81172932, 81273376]
- Natural Science Foundation of Jiangsu Province [BK2012356]
- State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKGZ201103]
Twelve novel dicoumarol glucagon-like peptide 1 (GLP-1) conjugates were designed, synthesized, and tested for biological activity. All derivatives retained receptor activation efficacy, and exhibited improved albumin affinity and in vitro stability in rat plasma. The in vivo elimination half-lives of 13c and 131 (22.07 and 18.78 h, respectively) were much longer than those of the GLP-1 receptor agonists exendin-4 (2.82 h) and liraglutide (12.53 h). The prolonged in vivo antidiabetic effects of 13c and 13l on db/db mice were confirmed by the hypoglycemic efficacy test and the multiple intraperitoneal glucose tolerance test. Importantly, a once daily administration of 13c to db/db mice for 7 weeks provided long-term beneficial effects by lowering glycated hemoglobin (HbAlc) levels to 5.05%, which was lower than with liraglutide treatment (5.41%). These results suggest that 13c is a promising long-lasting GLP-1 mimetic that may be suitable for clinical use following further research.
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