Design And Synthesis Of Selective PTP1B Inhibitors

Objective:Diabetes is a group of metabolic diseases characterized by chronic elevated blood glucose level, either because the tissues do not produce enough insulin or because cells fail to use insulin effectively. With the improvement in living standards, the incidence of diabetes grows rapidly, ranking the third largest diseases threatening human life after cardiovascular disease and cancer. Over 300 million people suffer from diabetes today, which will be expected to exceed half a billion by 2030, and 4.6 million. A numbers of novel receptors and enzymes related to diabetes pathogenesis have discovered. These targets provide a solid foundation for drug design and screening. Protein tyrosine phosphatase1B(PTP1B), a primary negative regulator in insulin signaling pathway, dephosphorylates phosphotyrosine residues of the active insulin receptor and insulin receptor substrates, and disrupts the insulin signal transduction. PTP1 B has become an important drug target on the treatment of type Ⅱdiabetes and obesity, and low molecule selective inhibitors of PTP1 B provide brilliant prospects for anti-diabetics discovery. Our objects focus on design and synthesize anti-diabetic lead compounds based on the structure of PTP1 B target enzyme.Methods:The structure characters of antidiabetic lead compounds were established by merging the structure of PTP-1B and TCPTP and the compounds database was built according to drug likeness, synthetic feasibility and structure character above, using molecular fragment from ZINC-drug-like. With the help of computer-aided drug design(CADD) technology, virtual screening of the compounds database was performed by using Glide which was embedded into Schrodinger Suite 2009. The designed compounds were docked into the receptors downloaded from PDB bank. By searching Reaxys database, a series of compounds were synthesized. With investigations for the synthesis optimization, and the purity and yield of the target compounds are improved. In the synthetic section, the synthetic routes were designed and the final compounds were obtained through the reactions of Wald reaction and nucleophilic substitution. These compounds were confirmed by 1H-NMR and MS.TLC was used to monitor the reaction in the synthetic process. Through extraction, filtration, column chromatography separation, 20 novel compounds are obtained in all. The target compounds were purified and then confirmed by 1H-NMR and MS. And the activity detection is ongoing.Results: A series of PTP1 B inhibitors are obtained through virtual screening of the PTP1B-target antidiabetic compounds database. Molecular docking studies show that these compounds are found to form hydrogen bonds and hydrophobic interaction with the key residues of the target, which indicates that these compounds have potential characters of PTP1B-target drug and can be recognized as antidiabetic lead compounds for PTP-1B. 20 final compounds which may have pharmacological activity were synthesized.Conclusion: This research selected PTP1 B as the target enzyme. Compounds formed hydrophobic interaction with the second binding sites of PTP1 B Asp48, Met258, Gly259 and Gln262 residues form effect, can improve the selectivity of inhibitors, which in accordance with the existing reports. The work of this paper may lay a foundation to discover leads compounds to treat type II diabetes and obesity.