Design racional de inibidores da enzima Dipeptidil peptidase IV (DPP-IV) beta-amino hidrazidas, beta-amino acilhidrazonas em modelos de resistência insulínica

Abstract

Diabetes mellitus (DM) is a metabolic syndrome that affects a worldwide population, with type 2 DM corresponding to about 90% of cases. Dipeptidyl peptidase IV (DPPIV) inhibitors belong to a class of oral antidiabetics called gliptins, known to have minimal adverse events. However, the long-term adverse effects of gliptins are poorly documented. Thus, improvements in the therapeutic effects and reduction of adverse effects of this class of drugs are necessary. In this sense, we investigated the activity and mechanism of action of DPP-IV inhibitors based on the fundamental structure of sitagliptin, on glucose metabolism and in animals with insulin resistance induced by dexamethasone (CEUA-NPDM 17010720-0). In the glucose tolerance test, the effect of the new DPP-IV inhibitors (LASSBio 2125, 2123, 2129 and 2130; 10 mg/kg, i.p.) on the glucose tolerance curve was examined: the hyperglycemic group showed increased glycemia with the passage of times of 15 and 30 min. Sitagliptin decreases glycemia at a dose of 10 mg/kg by 52.75% and 40.75% at times 15 and 30 min; respectively, when compared with the hyperglycemic group. Among the compounds, LASSBio 2129 stood out, which identified glycemia in 46.1% and 28.06% at times 15 and 30 min respectively, when compared to the hyperglycemic group. Furthermore, Lassbio-2129 increased muscle and liver glycogen content by 9.4 times and 1.86 times respectively. LASSBio 2129 treatment remarkably reversed insulin resistance induced by dexamethasone (0.1 mg/Kg s.c.). In this way LASSBio has been shown to regulate blood glucose and improve insulin resistance. The compound LASSBio 2129 may soon be needed for the treatment of type 2 diabetes.