Design,Synthesis And Biological Evaluation Of Protein Tyrosine Phosphatase-1B (PTP1B) Inhibitors

Protein Tyrosine Phosphatase-1B（PTP1B）,as a therapeutic target for the treatment of type 2 diabetes and obesity,has attracted tremendous attention since it was discovered.Studies on the development of novel PTP1B inhibtors have reached great progress for recent two decades.Despite the extensive research on PTP inhibitors,however,none of the inhibitors has been approved for clinical use,mainly due to their poor selectivities over other PTPs and the low bioavailabilities.As a result,it’s necessary to develop potent and selective PTP1B inhibitors.In this thesis,we designed Y-shaped bis-arylethenesulfonic acid esters as tridentate inhibitors.These novel molecules,particularly Y-shaped bis-arylethenesulfonic acid ester derivatives,exhibited high PTP1B inhibitory activity,moderate selectivity,and great potential in penetrating cellular membranes(compound 7p,P_app=9.6×10^-6 cm/s;IC₅₀=0.14,1.29 and 0.92μM on PTP1B,TCPTP and SHP2,respectively).Docking simulations suggested that these Y-shaped inhibitors might interact with multiple secondary binding sites in addition to the catalytic site of PTP1B.In order to improve the selectivity for PTP1B,we designed tridentate arylethenesulfonic acid esters derivatives（IV-A,IV-B,IV-C,IV-D series）,which contained arylethenesulfonic acid esters,hydrophobic groups and other PTyr mimetic such as salicylic acid group or 2-phenoxyacetic acid group.These four types of tridentate PTP1B inhibitors showed high activity and selectivity,especially that containing salicylic acid structure（IV-B,IV-C,IV-D series）.IC₅₀ values of most of these compounds are below 0.5μM and some of them are even below 0.2μM.These compounds also possess better selective over that of TCPTP and SHP2（>20 fold）.Compound 78p was found to be the most potent tridentate inhibitors against PTP1B(IC₅₀=0.03μM)and also had good selectivity over TCPTP（²3-fold）and SHP2（¹4-fold）.Docking studies on compounds 7P and 78P showed that the two arylethenesulfonicacid esters groups of 7P bind to the A site and C site,respectively,and the selectivity over TCPTP was probably due to the overall favorable interaction of the diphenyl ether group in the E site.The arylethenesulfonic acid ester group of 78P was found to binded to the B site,while the salicylic acid to the A site and the dodecyl benzene group to the C site,respectively.We also investigated whether the PTP1B inhibition exerted by compounds 7P and 78P result in enhanced insulin-stimulated glucose uptake in HepG2 cell.It was showen that compounds 7P and 78P can highly enhance insulin-stimulated glucose uptake in HepG2 cell.Parallel artificial membrane permeability assay（PAMPA）showed compound 7P has good membrane permeability.In summary,we designed and synthesized 113 arylethenesulfonic acid ester derivatives.The most potent compounds 7P and 78P showed good hypoglycemic effect in HepG2 cell.These two compounds have prompted for further evaluation as potential therapeutic PTP1B inhibitors.