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To develop novel long-acting antidiabetic agents, mycophenolic acid (MPA) was used to modify Xenopus glucagon-like peptide-1 analog (GLP-1) ( 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 1 . 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 1 derivatives ( 2a-2i ) were obtained. Compounds 2b and 2c , 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 3a-3d . The receptor activation potencies and hypoglycemic activities of 3a-3d were comparable to that of liraglutide. Physicochemical and in vitro stability tests revealed that MPA conjugation led to enhanced albumin binding abilities as reflected by the improved stabilities of 3a-3d . In particular, at a dose of 25 nmol kg -1 , the in vivo antidiabetic and insulinotropic activities of 3d were comparable to those of semaglutide. Finally, long-term administration of 3d 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.

Synthesis and pharmaceutical characterization of site specific mycophenolic acid-modifiedXenopusglucagon-like peptide-1 analogs