Design, Synthesis And Activity Evaluation Of Novel PPAR Dual Agonists

BackgroundPPARs have been recognized as an important target for the fight against diabetes because of its ability to control fat metabolism and regulate energy balance in the body.However,as the research progressed more and more,the researchers became more and more eye-catching.PPARs proteins are closely related to the body's various physiological activities,not just fat metabolism.Studies have shown that PPARs agonists have a role in the treatment of inflammation,cardiovascular disease,neurological disease,and even cancer,and pioglitazone-PPAR? agonists have been used in clinical ophthalmology treatment,for more in-depth research It will definitely help people overcome various diseases.In recent years,dual agonists of PPAR?/? have received increasing attention.At present,the dual agonists of PPAR?/? have been reported to be based on alkoxyphenylcarboxylic acids,phenoxycarboxylic acids and glycines,and their design combines the hydrophilicity of PPAR? and the lipophilicity of PPAR?.Connected by different chains.Representative compounds such as Tesaglitazar,Ragaglitazar,Aleglitazar,Muraglitazar,Saroglitazar,and the like.However,for the development of PPARs agonists,there are still many problems waiting to be solved.For example,the optimal proportion of excitement,the lack of novelty of the skeleton,and the like.Research objectiveIn this study,the computer-assisted drug design method was used to screen out the novel lead compounds,and then modified on the basis of the lead compounds to optimize the activity.Finally,the activity information was used to establish the structure-activity relationship for the future double agonists.The development provides assistance.Research methods1)Screening and activity determination of lead compounds: Two PPAR? and ?proteins and complex structures of their respective ligands were downloaded from the PDB database.The method of constructing a pharmacophore model based on active sites was used to explore the Discovery studio software.,build and select the best pharmacophore model.Existing databases were screened using the resulting pharmacophore model,including the ZINC,Chembl,and Drugbank databases.Theobtained small molecule was synthesized and tested for its biological toxicity,PPAR?/? agonistic activity.Structural transformation of pilot small molecules2)Renovate the lead compound and test the activity: use the DS software CDOCKER module to dock the obtained small molecule into the active pocket,explore its interaction mode,and design and transform according to its docking mode,in order to obtain better activity.Small molecule.3)Synthesize the designed small molecule and test its activity4)Establish a preliminary structure-activity relationship in the basis of the series of activities and structures.Research resultsThe molecular structure of this type of structure,the addition of a sterically hindered hydrophobic group at the phenyl 2 position to occupy the cavity can significantly increase the activity,and the effect of the chromone 2 position hydrogen bond acceptor group on the activity is crucial.The 3 position has no significant effect on the activity.