Design, Synthesis, and Biological Evaluation of 1,4-Dihydropyridine-Indole as a Potential Antidiabetic Agent via GLUT4 Translocation Stimulation.

In the quest for the discovery of antidiabetic compounds, a series of 27 1,4-dihydropyridine-indole derivatives were synthesized using a diversity approach. These compounds were systematically evaluated for their antidiabetic activity, starting with an in vitro assessment for GLUT4 translocation stimulation in L6-GLUT4 myc myotubes, followed by in vivo antihyperglycemic activity evaluation in a streptozotocin (STZ)-induced diabetic rat model. Among the synthesized compounds, 12 , 14 , 15 , 16 , 19 , 27 , and 35 demonstrated significant potential to stimulate GLUT4 translocation in skeletal muscle cells. Compound 19 exhibited the highest potency and was selected for in vivo evaluation. A notable reduction of 21.6% ( p < 0.01) in blood glucose levels was observed after 5 h of treatment with compound 19 in STZ-induced diabetic rats. Furthermore, pharmacokinetic studies affirmed that compound 19 was favorable to oral exposure with suitable pharmacological parameters. Overall, compound 19 emerged as a promising lead compound for further structural modification and optimization.