Design And Synthesis Of Novel PPARα/γ Dual Targeted Agonists

Objective: Diabetes is a metabolic syndrome characterized by hyperglycemia.For the past few years,the morbidity and mortality of diabetes have been keeping high.Peroxisome proliferator-activated receptors(PPARs)are ligand-activated receptor in the nuclear receptor family,including three subtypes: PPARα,PPARβ/δ,and PPARγ.Some diseases such as diabetes and dyslipidemia are closely related to PPARs.PPARα agonists Fibrates are lipid-lowering drugs,which might lead to adverse effects such as abdominal pain and renal failure.Thiazolidinediones that activate PPARγ belong to anti-diabetic drugs.The function of activating PPARγ can increase insulin sensitivity and lower blood glucose levels.However,there are still side effects such as hepatotoxicity,water retention and weight gain in clinical treatment.The selective single PPARs agonist might produce some unavoidable adverse effects.In recent years,medicinal chemists pay more attention to the research on multi-targeted PPARs agonists.PPARα/γ dual agonists can regulate dyslipidemia and pathoglycemia.Based on the current PPARs agonists,this paper using computer-aided drug design technology and traditional chemistry methods screened,designed and synthesized PPARα/γ dual agonists.It lays the theoretical foundation for novel high-efficiency and low-toxicity hypoglycemic drugs.Methods:(1)With computer-aided drug design,we hope to gian the effective and safe PPARα/γ dual agonist from Ligand Expo Components database by high virtual screening,precise docking,AMDET prediction and molecular dynamics simulation using Discovery Studio 3.5 and Schr?dinger Suite 2015 software.(2)Based on the combination principle in medicinal chemistry,the polar head of the bezafibrate(PPARα agonist)and the hydrophobic tail of the rosiglitazone(PPARγ agonist)were integrated to obtain a new molecule.The structure of molecule was optimized in order to design PPARα/γ dual agonists.The docking method in computer-aided drug design was used to study the rationality of the designed compounds.(3)The intermediates XY9014-1 and XY9016-1 were synthesized by reaction of hydroquinone and resorcine with ethyl bromoacetate.The intermediates reacted with halides of different substituents to form ester compounds.Finally,a series of carboxylic acid compounds were obtained by hydrolysis reaction.Results:(1)In this paper,the potential PPARα/γ dual agonist M80 was obtained by screening the Ligand Expo Components database.Compared with the original ligands,the compound M80 has higher docking score,better binding mode,more stable interactions,better pharmacokinetic properties and lower toxicity.(2)Based on the combination principle,the polar head of bezafibrate and the hydrophobic tail of rosiglitazone were combined in one molecule,and nine PPARα/γ dual agonists were designed.It is shown that the designed compounds have the similar docking scores and more hydrogen interactions compared with bezafibrate and rosiglitazone.It verified the strucutral rationality of the designed compounds.According to the docking results,the feasibility of subsequent synthesis experiments on the designed compounds was determined.(3)The designed compounds were subjected to synthesis experiments,and we obtained nine compounds of carboxylic acids.The structures of synthesized compounds were confirmed by NMR and MS.Conclusion: In this paper,based on PPARα and PPARγ,we used computer-aided drug design technology and traditional synthesis experiments to discover,design and and synthesize ten PPARα/γ dual agonists.The structures of nine synthesized compounds have been confirmed.The work of this paper provides a valuable reference for the development of potential PPARα/γ dual agonists with high-efficiency and low-toxicity.