The Study Of The Structural Modification, PPAR Signaling Pathway Screening And The Physicochemical Properties Of Thiazolidinediones Drugs

In recent, with the development of living standard, our livingenvironment and dietary structure have greatly changed. The prevalence ofdiabetes sets to rise dramatically in the whole world. Diabetes is dividedinto type1diabetes and type2diabetes,90%of which catch type2diabetes.Therefore,we are most to treatment type2diabetes.Type2diabetes is coursed by the insulin resistance and the damageof pancreatic β cells function. Thiazolidinediones drugs can reduce insulinresistance and restore insulin function by activating the peroxisomeproliferator-activated receptor γ. Consequently, it could protect pancreaticβ cells. Compared with the traditional antidiabetic drugs, It conforms to thenew treatment concept.In spite of many advantages are thiazolidinediones, some adversereactions occurred with thiazolidinediones drugs widely used, such asweight gain, edema, osteoporosis and anemia, even the exacerbationcongestive heart failure, These adverse reactions have limited its clinical application. Therefore, the structure of Rosiglitazone was modified byapplication of basic principles of drug design in order to acquire the PPARγagonist with fewer adverse reactions.Our work was described as follow:1. Referring relative literature and our past reserchs, the adversereaction of rosiglitazone comes from the fully agitating PPARγ. Theadverse reaction can be lessened as full agonist turning into partial agonistor selective PPARγ modulator（SPPARγM）, if the halide with reactiveα-H was used to substitute with3-H on N of thiazolidinedione. So wedesigned nine3-N substituted rosiglitazones.2. Assayed pKa of those rosiglitazone derivatives to understandrelationship of their fundamental physical and chemical properties withbiological activity.3. Determined content of rosiglitazone derivatives by HPLC,Determined the structure of the nine rosiglitazone derivatives by IR,1H-NMR and other methods. And the structure of RSG-9wasascertained by x-monocrystal diffraction.4. In the model of selectivity PPAR regulator, we have made a signalchannel activity screening for rosiglitazone derivatives. The resultsshowedthat: the compound of RSG-9has activty.In summary, we synthesised nine of rosiglitazone derivatives by thealkylated reaction of SN. The new rosiglitazone derivatives wasCharacterizated by HPLC, IR,1H-NMR and x-monocrystal diffraction. screened the signal channel activity and studied the physico-chemicalproperties, the results achieve the purpose of the design and requirementsfor this article.