Peroxisome proliferator-activated receptor Î³ (PPARÎ³) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARÎ³ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARÎ³. Furthermore, docking experiments revealed that BTZDs interact with PPARÎ³ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPARÎ³ for further development in the clinical treatment of type 2 diabetes mellitus.
|Titolo:||Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARÎ³ Agonists and their Antidiabetic Effects on Type 2 Diabetes|
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||1.1 Articoli su Rivista|