Recent Medicinal Chemistry Approach for the Development of Dipeptidyl Peptidase IV Inhibitors

Diabetes, a metabolic disease, occurs due to a decreased or no effect of insulin on the blood glucose level. The current oral medications stimulate insulin release, increase glucose absorption and its utilization, and decrease hepatic glucose output. Two major incretin hormones like Glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide - 1 (GLP-1) stimulate insulin release after a meal, but their action is inhibited by enzyme dipeptidyl peptidase- IV.

The activity of endogenous GLP-1 and GIP prolongs and extends with DPP IV inhibitors, which are responsible for the stimulation of insulin secretion and regulation of blood glucose level. DPP IV inhibitors have shown effectiveness and endurability with a neutral effect on weight as well as less chances of hypoglycemia in the management of type 2 diabetes. These journeys started from Sitagliptin (marketed in 2006) to Evogliptin (marketed in 2015, Korea).

Treatment of type 2 diabetes includes lifestyle changes, oral medications, and insulin. Newer and superior therapies are needed more than currently prescribed drugs. Various heterocyclic derivatives have been tried, but due to masking of DASH proteins, CYP enzymes, and hERG channel, they showed side effects. Based on these, the study has been focused on the development of safe, influential, selective, and long-lasting inhibitors of DPP IV.