Synthesis and pharmaceutical characterization of site specific mycophenolic acid-modified glucagon-like peptide-1 analogs.

To develop novel long-acting antidiabetic agents, mycophenolic acid (MPA) was used to modify glucagon-like peptide-1 analog (GLP-1) () at three Lys residues through a γ-glutamyl linker. Similarly, 6-aminocaproic acid and 12-aminolauric acid with different lengths of fatty chain were used as MPA derivatives which were then conjugated with . By using proper protection and deprotection strategies, the synthetic process was completed directly on the resin to minimize the side reactions, and nine MPA-modified derivatives () were obtained. Compounds and , which showed high GLP-1 receptor activation potencies and glucose lowering activities, were selected for further C-terminal modification to improve their stabilities and bioactivities, giving compounds . The receptor activation potencies and hypoglycemic activities of were comparable to that of liraglutide. Physicochemical and stability tests revealed that MPA conjugation led to enhanced albumin binding abilities as reflected by the improved stabilities of . In particular, at a dose of 25 nmol kg, the antidiabetic and insulinotropic activities of were comparable to those of semaglutide. Finally, long-term administration of achieved beneficial effects on glucose tolerance normalization and glycated hemoglobin (HbA1c) lowering, and no hepatotoxicity was observed. In conclusion, this research demonstrated that MPA derivatization was a practical way to develop long-acting antidiabetic peptides.