Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists.

摘要: Abstract Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing global public health burden affecting more than 366 million people worldwide. We recently reported the discovery three series novel agents showing balanced activity on two receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied linking thiazolidinedione head with GPCR privilege structures. To further investigate this concept, new scaffolds, benzhydrol- indole-based chemotypes, were introduced here in. optimization campaign resulted in compounds; 15a, 15c, 15d, affinities low micromolar range both targets. In vivo study selected test compounds, revealed that 15c possesses significant anti-hyperglycemic anti-hyperlipidemic activities superior to rosiglitazone fat-fed animal models. Molecular docking analysis was conducted explain binding modes series. These compounds could lead development unique antidiabetic agent acting insulin sensitizer well secretagogue.