Design And Synthesis Of PTP-1B Inhibitors Based On Imidazolidinedione Scaffold

Objective:Diabetes is a group of chronic syndrome with feature of glyco-metabolism disorder,which results from absolutely or relatively insufficient of insulin.Remarkable progress has been made on the research of drug targets at the molecular and cellular level,which has discovered a number of novel receptors and enzymes related to diabetes pathogenesis.These targets provide a solid foundation for drug design and screening.As the primary negative regulator in insulin signaling pathway,protein tyrosine phosphatase-1B(PTP-1B)dephosphorylates phosphotyrosine residues of the active insulin receptor and insulin receptor substrates,and disrupts the insulin signal transduction.PTP-1B has become an important drug target on the treatment of type ? diabetes and obesity.And the low molecule inhibitors of PTP-1B provide brilliant prospects for anti-diabetics discovery.Some PTP-1B inhibitors were designed and synthesized in order to identify lead compounds with better antidiabetic activity and lower toxicity.Our research focus on design and synthesis of anti-diabetic lead compounds based on the structure of PTP-1B target enzyme.Methods:Some imidazolidine-2,4-dione derivatives were designed as PTP-1B inhibitors by starting from the structure of thiazolidinedione class PTP-1B inhibitors and using bioisosterism principle in medicinal chemistry.With the help of Computer-Aided Drug Design technology,PTP-1B crystal structure from the protein database were downloaded for docking receptors.The designed compounds were docked into the receptors and then screened to identify potencial lead compounds.Starting from benzylhydantoin,hydroxybenzaldehyde,methyl bromoacetate and methyl 4-(bromomethyl)benzoate as the raw material,the target compounds were obtained by chemical synthesis and their structures were confirmed by 1H-MMR.Results:Molecular docking studies suggest that the imidazolidinedione derivatives could play an important role by insersting into the active sites of PTP-1B.In the meanwhile,the docking scores for receptors-ligands are satisfactory,which were obtained from all kinds of docking energies,in hoping that these compounds may hold the potential to inhibit the receptor.The optimum synthesis conditions were studied,and 24 novel compounds are obtained through the Knoevenagel Reaction and the nucleophilic substitution,with a high level of product purity and yield.The target compounds were purified and then confirmed by 1H-NMR.And the activity detection is on going.Conclusion:Selecting PTP-1B as the target enzyme,the imidazolidinedione scaffold based PTP1B inhibitors were designed.The designed compounds were screened using the CADD technology,and some potencial lead compounds were identified.By chemical synthesis,24 imidazolidinedione class PTP-1B inhibitors were obtained and confirmed by 1H-MMR.Further activity studies were underway.