A perspective on the development of small molecular neprilysin inhibitors (NEPi) with emphasis on cardiorenal disease

Abstract

Neprilysin is a cell surface metallo-endopeptidase, commonly identified as neutral endopeptidase (NEP), that plays a crucial role in the cleavage of peptides, for example, natriuretic peptides, angiotensin II, enkephalins, endothelin, bradykinin, substance P, glucagon-like peptide and amyloid beta. In the case of heart failure, a significant upsurge in NEP activity and expression enhances the degradation of natriuretic peptides. Therefore, NEP inhibitors have gained attention in the field of cardiology. NEP has been studied for over 40 years; however, it has recently gained attention with the US FDA approval of a fixed dose combination of sacubitril (NEP inhibitor) and valsartan (AT-1 inhibitor) for chronic heart failure treatment. The present review elucidates the role of neprilysin in cardiorenal disease, its pathophysiology, and how NEP inhibition benefits. It also summarizes the research advances in NEP inhibitors (NEPi) and their structure-activity relationships. Moreover, the review provides insight into NEPi effectiveness - alone or combined with other cardiorenal protective agents. It is expected to help medicinal chemists synthesize and develop novel NEPi.