title: Design, synthesis, and biological activity of novel dicoumarol glucagon-like peptide 1 conjugates.
abstract: 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 13 l (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 13 l 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 (HbA1c) 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.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Lidan
authors.initials: L
authors.lastname: Sun
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Dandan
authors.initials: D
authors.lastname: Huang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Zhu
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D003374:Coumarins / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry*; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000187:drug effects; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry
chemical_list: D003374:Coumarins; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D012709:Serum Albumin; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat