IMB-05

In our previous study, two synthetic thiophenes such as IMB-05 and IMB-15 were found as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and exhibited beneficial effects on glucose tolerance of diabetic mice in vivo. In the present study, their effect on the transactivity of other nuclear receptors was further investigated. IMB-05 and IMB-15 could not only activated PPARγ but also efficiently activate PPARα in GAL4-hPPARα/γ (ligand binding domain (LBD)) chimeric receptor assay and PPAR response element (PPRE)-luc reporter gene assay with EC(50) values of 1.8-5.2 µM, whereas no activity was observed in other nuclear receptor assays. In addition, the maximal efficacy of IMB-05 and IMB-15 in activating PPARα/γ was approximately 30% of that observed with Wy14643 and rosiglitazone. These data indicate that the two thiophene derivatives are novel class of partial PPARα/γ dual agonists, which may be the mechanism underlying their regulatory effects on glucose homeostasis.

Eighteen substituted thiophene and benzothiophene derivatives were studied for their effects on peroxisome proliferator-activated receptor γ (PPARγ) in HepG2 cells.Three derivatives (compounds 5, 120.97%; 15, 102.14%; and 17, 113.82%) were found to transactivate PPARγ in vitro.By comparison, the pos. control rosiglitazone (Ros) transactivated PPARγ by 311.53%.The three compounds were studied for their effects on glucose metabolism in vivo in KK/Ay diabetic mice.In vivo, the 2-(β-carbonyl/sulfonyl) butyryl-thiophene compounds 5 and 15 significantly decreased blood glucose levels (compounds 5, to < 15.6 mmol/L; 15, to < 10 mmol/L), improved glucose tolerance, improved impaired pancreatic islet β-cells, and lowered serum insulin levels.