Computational Simulation Studies, Synthesis, <i>In Vitro</i>, and <i>In Vivo</i> Evaluation of Heterocyclically Substituted Glycinamide Derivatives as DPP 4 Inhibitors

Abstract According to the International Diabetes Federation, the global prevalence of diabetes is projected to increase to 643 million individuals by 2030 and 783 million by 2045. DPP 4 inhibitors approved by regulatory authorities worldwide, efficiently to regulate high blood sugar levels by impeding the degradation of glucagon like peptide‐1 (GLP‐1), an incretin hormone, prolonging the physiological effects of GLP‐1. In the present research work, a total of 12 glycinamide‐based compounds with aromatic substituents on the N‐terminus and heterocycles like piperidine, 4‐phenylpiperazine, and 6‐fluorobenzo[ d ]isoxazol‐3‐piperidine on the C‐terminus were synthesized and characterized. The synthesized compounds were subjected to in vitro DPP 4 inhibition assay. The promising compound JAG‐D2 was evaluated in vivo using OGTT assay in streptozotocin‐induced diabetic rats. JAG‐D2 produced a significant reduction in blood glucose levels at 20 mg/kg and 40 mg/kg doses when compared with a 1 mg/kg dose of the reference standard sitagliptin. The synthesized compounds occupied the active site of DPP 4 as demonstrated in molecular docking and MM‐GBSA analysis for rescoring on the basis of binding free energy. Molecular dynamics studies displayed the stability of the docked pose of JAG‐D2 in the catalytic site of DPP 4. All compounds exhibited compliance with Lipinski's rule of five, suggesting drug‐like properties.