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

ABSTRACT

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-GLUT4myc 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.