Structure-Based Design, Sythesis And Screening Of PPARδ Agonists

Several lines of evidence suggest that metabolic diseases of modern society are associated with high-fat diets combined with a sedentary lifestyle. For example, diabetes, obesity and cardiovascular disease are major causes of mortality and morbidity whose incidence tracks with the rate of industrialization in many countries. metabolic diseases, such as diabetes, dyslipidemia, obesity and cardiovascular disease, have been expanding health threat. Peroxisome proliferator-activated receptors (PPARs) have attracted enormous attention due to the key role these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation and blood pressure.PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. There are three PPAR subtypes encoded by distinct genes: PPARα(NR1C1), PPARγ(NR1C3) and PPARδ (NR1C2). Fibrates drugs that lower triglyceride levels and raise HDL have been found to activate PPARα. PPARγ agonists - thiazolidinediones improve insulin sensitivity and have been used for treatment of type 2 diabetes. The role of the third member the PPARs family, PPARδ, remained elusive untile recently. These past few years, the availability of special PPARδ agonists and of appropriate cellular and animal models revealed that activation of PPARδ promotes fatty acid burning in skeletal muscle and adipose tissue by upregulation of fatty acid uptake, β-oxidation and energy uncoupling. Additional studies showed that PPARδ agonist promotes reverse cholesterol transport and raises HDL-c in serum while lowering the level of LDL-c. Besides, PPARδ controls the inflammatory status of macrophages and thus may be a good target for treating atherosclerosis. These observations strongly suggest that PPARδ agonists may provide a new approach to the treatment of metabolic diseases.Based on the structure of PPARδ and the interactive characteristics of ligands with PPARδ, a novel virtual library of PPARδ agonists was constructed in a combinatorial...