PPARγ Non-agonist Ligand:The Structure Optimization Based On PPARγ Partial Agonist

Diabetes is a group of metabolic diseases characterized by hyperglycemia and type 2 diabetes has above 95%in all diabetes,thiazolidinedione drugs(TZDs)are the only effective insulin sensitizer for type 2 diabetes.However,TZDs had limited in clinical by some adverse side effects.With the intensive study of PPARγ,recent studies showed a new mechanism of reducing blood glucose that insulin-sensitizing activity of TZDs occurs through the inhibition of PPARγSer273 phosphorylation mediated by cyclin-dependent kinase 5(Cdk5),which resultes from the binding activity for PPARγ,whereas the side effects of TZDs could be related to the agonistic potency for PPARγ.Therefore,we can design a PPARγnon-agonist by optimizing the structure of PPARγpartial agonist.In other words,the highly effective oral medications for type 2 diabetes have insulin-sensitizing activity while the side effects of TZDs are disappear.According to the binding mode of INT131 in their crystal structures,we designed and synthesized three types structure include 24 sulfamide compounds targeted on PPARγby computer aided drug design and bioisosterism.These compounds have been confirmed by~1H NMR and LC-MS.We have completed the evaluation of transactivation and binding activity of these compounds on PPARγ.It was found that most compounds have higher binding activity and lower transactivation of PPARγ.In especially,the binding activity of ZY-17 is equal INT131,but the transactivation of ZY-17(1.41%)compared with INT131(15.18%)is close to disappear.The compound ZY-17 can further study as a lead compound.The conclusion of experimental date and structure-activity relationship of these compounds can be an important basis and reference for the following research.