Discovery of Hypoglycemic and Cardiovascular Drugs as Effective Inhibitors on Human Pancreatic Lipase.

Obesity is closely related to the occurrence and development of many diseases, such as diabetes, hypertension, and hyperlipidemia. As an important digestive enzyme, human pancreatic lipase (hPL) is involved in the metabolism and absorption of dietary fat and is a key target of overweight and obesity. Therefore, the inhibition of hPL enzyme is a feasible strategy for the prevention and treatment of obesity. In this study, we collected a series of marketed hypoglycemic and cardiovascular drugs and evaluated their inhibitory activity against hPL. Among them, ticagrelor (HC-14), prasugrel (HC-18), amlodipine (HC-26), simvastatin (HC-32), and lovastatin (HC-33) had strong inhibitory activity against hPL. In order to further clarify the inhibition mechanism, inhibition kinetics and molecular docking were carried out, and results revealed that HC-14 was a mixed inhibitory manner on hPL activity. HC-14 also showed similar inhibitory effect on human carboxylesterase 2 (hCES2), but poor inhibitory effect on other five serine hydrolases. Further studies showed that HC-14 significantly inhibited hPL activity in AR42J cells, resulting in dose-dependent inhibition. Overall, the above results suggest that ticagrelor is a cardiovascular drug that inhibits hPL, which also provides an important reference for the search and development of other drugs for the treatment of obesity.