Study On The Synthesis Of The Dipeptidyl Peptidase-â…£ Inhibitor K579

Type-2 diabetes mellitus is a chronic metabolic disease and a growing global public health concern. In the world, more than 285 million adults and children have diabetes. Current oral treatment modalities for type-2 diabetes are aimed at suppressing hepatic glucose output, stimulating insulin release, mitigating glucose absorption, and increasing peripheral glucose utilization. Inhibition of the dipeptidyl peptidase-4 (DPP-4), a member of the prolyl oligopeptidase family of serine protease, prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation. Inhibition of DPP-4 enzyme by small molecules has emerged as one of the key approaches for the treatment of type-2 diabetes. A large number of DPP-4 inhibitors have been reported in the literature.K579, [(S)-1-[4-methyl-1-(2-pyrimidinyl)-4-piperidylamino]acetyl-2-pyrrolidine carb onitrile], is a DPP-4 inhibitor discovered by researchers at Kyowa Hakko Kyogo. It didn't only have improved chemical stability but also a longer-lasting action. That long-lasting action was most likely due to slow dissociation of the enzyme-inhibitor complex and an active oxide metabolite that undergoes enterohepatic circulation. The discovery of the active oxide was in fact a large breakthrough as it led to the development of vildagliptin and saxagliptin. Presently, saxagliptin is available for clinical use and vildagliptin has been launched in Europe only.The key intermediate tert-butyl-4-amino-4-methylpiperidine-1-carboxylate was prep -ared starting from ethyl piperidine-4-carboxylate via N-Boc protection, alkylation, amidation and Hofmann rearrangement. After condensation with two key intermediates which are 2-Chloropyrimidine and (S)-1-(2-chloroacety1)pyrrolidine-2-carbonitrile via two different synthesis, the target compound as lightyellow solid was obtained. The total yield of the process 1 was 33.5% , which is higher than that reported in the literature (29.0%), but the total yield of the process 2 was only 24.6%. The structure of the target compound was confirmed by 1H-NMR, MS and IR. The improved process reduced the use of expensive raw materials and toxic reagents with relatively convenient operation procedure and was more suitable for large scale industrial production.The interaction mode was studied between the target enzyme DPP-4 and a few of cyano-pyrrolidine derivative of DPP-4 inhibitors which are selected from the current market and in various clinical stages. The results showed that The target compounds K579 was very close to listed drugs, and even better than some of drugs in various clinical stages, which is expected to enter clinical stage and become a listed drug.