Structure-Based Design, Sythesis And Screening Of The Dual PPARα/γ Agonists

Type 2 diabetes is a multifactorial disease characterized by insulin resistance and/or abnormal insulin secretion. Type 2 diabetes and insulin resistance are frequently associated with dyslipidemia and a markedly increased incidence of atherosclerotic cardiovascular disease. Owing to the forecasted epidemic in type 2 diabetes, the increasing financial and social costs, and the complicated pathology of the disease, new therapies that address both the insulin resistance and dyslipidemic components of the disease are clearly in high demand.The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. There are three PPAR subtypes encoded by distinct genes: PPARa (NR1C1), PPARβ (NR1C2), and PPARγ (NR1C3). These receptors are important regulators in multiple physiological pathways, such as glucose homeostasis, fatty acid metabolism, inflammation, and cellular differentiation. PPARy is the molecular target for the thiazolidinedione (TZD) class of insulin sensitizing antihyperglycemic agents. Two of the TZDs, pioglitazone and rosiglitazone, have been used for treatment of type 2 diabetes. PPARa is the molecular target for the fibrates (e.g. fenofibrate and clofibrate) which primarily decrease serum triglyceride levels and increase HDL cholesterol (HDLc) levels. New dual PPARα/γ agonists, designed to combine the beneficial effects of insulin sensitizers and fibrates, might also reduce the weight gain associated with adipogenesis resulting from PPARy activation through the simultaneous stimulation of lipid oxidation and decreased adiposity observed after PPARa activation.On the basis of the PPARα/γ receptor complex with the dual agonist GW409544, we used the program InsightⅡ to simulate the interaction between compounds and ligand binding domain, designed and synthesized six sets of 61 L-tyrosine derivatives whose structures were justified with NMR and MS methods.The results of in vitro assay indicated that 10 target compounds have a higher or equal PPARα/γ dual-agonistic activity compared with rosiglitazone. The effects of the compound P518H were investigated in normal KM mice, hyperlipidaemia mice and db/db mice by gavage, the results indicated that P518H can reduce blood lipid level and improve glucose metabolism.