Synthesis And Activity Studies Of Peptidomimetic DPP-IV Inhibitors Containing Amino Acid Structure

Type II diabetes is a chronic non communicable disease,characterized by hyperglycemia,hyperinsulinemia and insulin resistance,and it will bring serious damage to many systems of the body with the passage of time.Glucagon-like peptide(GLP-1)has glucose-dependent hypoglycemic action,and is degraded rapidly by DPP-IV enzyme.DPP-IV inhibitors can reduce the degradation of Endogenous GLP-1by DPP-? Enzyme1 and prolong the duration of GLP-1 to achieve hypoglycemic effects.Most of the DPP-IV inhibitors have an amide peptide bond structure in which the carboxylic acid moiety is a substituted a-or beta-amino acid,and the amine of the amide is mostly in the heterocyclic structure,and many drug molecular structures contain electron-withdrawing cyano substituted pyrrolidine.According to the structural characteristics of DPP-? inhibitors and the binding sites of DPP-? activity,a class of compounds containing amino acid and pyrrolidine-2-carbonitrile were designed as candidate molecules of DPP-IV inhibitors based on our preliminary work.The important raw materials(2S)-pyrrolidine-2-carbonitrile was synthesized by using L-proline as the starting material via a series of chemical reactions,such as amino protection,amination,dehydration and deprotection.And its synthesis process was optimized.With(2S)-pyrrolidine-2-carbonitrile and protected serine,lysine,cysteine,glusate by condensating and deprotecting,we have synthesized four target compounds:(S)-1-(L-seryl)pyrrolidine-2-carbonitrile,(S)-1-(L-cysteinyl)pyrrolidine-2-carbonitrile,(S)-1-(L-lysyl)pyrrolidine-2-carbonitrile,((2S)-2-amino-glutaryl)-bis((2S,2'S)-2-Cyanopyrrolidine).Finally,these target compounds have been prepared and they were not reported in the literature.The chemical constitutions of intermediate and target compounds were identified by 1H NMR and 13 C NMR and IR.The inhibition of target compounds on enzyme DPP-IV was detected in vitro by using DPPIV-Glo ? Protease Assay Kit.The results show that the inhibition of targetcompound 4d on enzyme DPP-? is more effective.The IC50 of compound 4d is 5.8nM,which is lower than the IC50 of positive control drug Sitagliptins(7.3 nM).So compound 4d has the possibility of studying in the future.