Neprilysin, cardiovascular, and Alzheimer's diseases: the therapeutic split?

Abstract

Neprilysin (also known as the neutral endopeptidase, EC 3.4.24.11) is a ubiquitous transmembrane and circulating protease with a broad range of substrates. Those include natriuretic peptides (NPs), vasoactive peptides (e.g. endothelin-1, bradykinins), neuropeptides (e.g. substance P, enkephalins), and the β-amyloid (Aβ) peptide amongst others.1,2 Given the central role played by neprilysin in the metabolism of cardiovascular peptides and the Aβ peptide, neprilysin has emerged as a pharmaceutical target of interest, both in the fields of cardiovascular disease (CVD) and Alzheimer's disease (AD). However, the strategies deployed in each field are completely opposite and one may wonder the rationale of neprilysin as a practical pharmaceutical target after all, since the populations suffering from CVD and AD are overlapping. In cardiovascular diseases, neprilysin gained interest as responsible for the degradation of NPs and other cardiovascular peptides.2 The development of neprilysin inhibitors (NEPi) have aimed at prolonging and potentiating the beneficial effects of vasoactive/NPs. However, since neprilysin has a broad range of substrates with antagonist effects (vasoconstrictor and vasodilator), the use of sole NEPi (candoxatrilat) was ineffective for the treatment of hypertension due to an aldosterone-independent increase in Angiotensin II.3 To overcome this limitation, NEPi were combined either with an inhibitor of angiotensin-converting enzyme (ACEi, e.g. omapatrilat4) or an angiotensin-receptor blocker (ARB, LCZ6965). Both omapatrilat6 and LCZ6967 were found, respectively, superior to enalapril (ACEi) and valsartan (ARB), for the treatment of hypertension. In the recent PARADIGM-HF trial, chronic administration of LCZ696 was found superior to enalapril for improving outcome in the treatment of chronic heart failure with reduced ejection fraction ( Figure 1 ).5 Recently, this beneficial effect on …