Resumen de Chapter Seven - Discovery and Development of Prolylcarboxypeptidase Inhibitors for Cardiometabolic Disorders

Sarah Chajkowski Scarry, John M. Rimoldi

• Abstract The serine protease prolylcarboxypeptidase (PRCP) is a unique exopeptidase with regulatory functions in the renin–angiotensin system, the kallikrein–kinin system (KKS), and in hypothalamic proopiomelanocortin downstream processing of alpha-melanocyte-stimulating hormone (α-MSH1–13). PRCP levels have been linked to hypertension, inflammation, and metabolic disorders such as obesity and diabetes. The regulation of hypothalamic melanocortin signaling (via PRCP inhibition of α-MSH1–13 inactivation) represents a novel therapeutic approach in the development of antiobesity agents. Using a combination of rational design approaches and high-throughput screening efforts, a number of potent and protease-selective PRCP inhibitors have been identified and evaluated in animal models.