Design,Synthesis And Biological Evaluation Of Tridentate PTP1B Inhibitors

Since its discovery,protein tyrosine phosphatase 1B(PTP1B)has been considered as a promising drug target for the treatment of type II diabetes and obesity.In recent 20 years,great progress has been made in the development of PTP1 B inhibitors and various novel PTP1 B inhibitors have been developed for further pharmacological research.However,the selectivity of these PTP1 B inhibitors is poor due to the high homology between PTP1 B and other PTPs.In addition,most of PTP1 B inhibitors suffered drawbacks of low bioavailability and poor cell permeability.Therefore,there is still a long way for the development of new PTP1 B inhibitors with high selectivity and good cell permeability.To solve these two problems,a series of stereoisomeric pyrrolidine bisarylethenesulfonic acid esters were designed and synthesized as tridentate PTP1 B inhibitors.Next,other kinds of p Tyr analogues were introduced to design and synthesize tridentate PTP1 B inhibitors.After considering the influence of chirality and different p Tyr analogues,we expect to obtain some novel tridentate PTP1 B inhibitors with high activity and selectivity as well as good membrane-permeability.Firstly,a series of chiral PTP1 B inhibitors were designed based on the pyrrolidine as the core scanffold.A total of 74 cis-and trans-compounds were synthesized and their PTP1 B activity and structure-activity relationships were investigated.The result showed that the activity and selectivity of trans-isomers were obviously superior to cis-isomers.Docking simulation explained the reason why the activity and selectivity of trans-isomers are higher than cis-isomers.For trans-derivative 11-17 which showed the best PTP1 B activity and selectivity,a series of in-depth experiments were carried out.We tested and verified the low cytotoxicity of compound 11-17 and the effects of compound 11-17 on insulin-stimulated glucose uptake and insulin-mediated insulin receptor β(IRβ)phosphorylation.Parallel artificial membrane experiment also showed that it has good membrane permeability.Therefore,trans-derivative 11-17 is an excellent leading compound for PTP1 B target.Secondly,in order to further optimize the lead compound Ⅱ-9(Fig.3-1,Chapter3)found by our team earlier,a series of tridentate PTP1 B inhibitors with two different p Tyr analogues were designed and synthesized,expecting to further improve the activity and selectivity of the inhibitor.Therefore,five series of these derivatives were constructed,which have 74 compounds in total.Among these compounds,Ⅱ-B series of compounds showed the best PTP1 B activity and selectivity as well as good membrane permeability.Enzyme kinetic experiments showed that these compounds are competitive inhibitors.For compound 30-3 which showed the best PTP1 B activity and selectivity in these compounds,we carried out a series of other experiments.Docking simulation experiment calculated the binding mode and explained the reasons for high inhibitory activity and selectivity of compound 30-3.Further biological experiments also showed that compound 30-3 has low toxicity and good hypoglycemic effect.In conclusion,a series of tridentate PTP1 B inhibitors designed and synthesized in this thesis showed high PTP1 B activity and selectivity as well as good cell membrane permeability.The compounds 11-17 and 30-3 also showed a good hypoglycemic effect in the biological experiments.This result could provide us an opportunity for the discovery of novel PTP1 B inhibitors with high activity and selectivity as well as good membrane permeability for future study.