Vasopeptidase inhibitors

Abstract

Vasopeptidase inhibitors are a new class of cardiovascular drug that simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II. In animal models vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease. Studies in human hypertension show that these agents are effective in decreasing blood pressure regardless of race or age. Experience with omapatrilat, the most clinically advanced of these drugs, has shown it to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. Studies with omapatrilat in congestive heart failure have shown beneficial effects on haemodynamics and symptoms. The vasopeptidase inhibitors appear to have safety profiles similar to ACE inhibitors, though the frequency of side-effects such as angio-oedema and cough remains to be established. Large trials with clinical endpoints, some already in progress, are needed to establish the place of this class of drug beside that of established therapies in conditions such as hypertension, heart failure, ischaemic heart disease, and nephropathy.

Reinventing the ACE inhibitors: some old and new implications of ACE inhibition

“…Neutral endopeptidase, a zincmetallopeptidase, degrades vasodilatory and diuretic natriuretic peptides that reduce volume loading and are therefore beneficial in both hypertension and heart failure. 184 As expected, omapatrilat has shown better results than ACEis in clinical trials, but recent larger clinical trials have revealed a problematic incidence of angioedema with omapatrilat. 185,186 Both ACE and neutral endopeptidase inhibit bradykinin degradation, and bradykinin has been implicated in the angioedema associated with ACE inhibition.…”

Next generation multifunctional angiotensin receptor blockers

“…However, the full potential of neprilysin inhibition was only realized in combination with concomitant inhibition of the angiotensin-converting enzyme (ACE), which culminated in the discovery and development of the vasopeptidase inhibitors, compounds that combined both neprilysin and ACE inhibitory activity in a single small molecule. 46 The clinically most advanced vasopeptidase inhibitor was omapatrilat, which was discovered and developed by Bristol-Myers Squibb (New York, NY, USA). Clinical hypertension trials have shown broadly Next generation multifunctional angiotensin receptor blockers TW Kurtz and U Klein superior antihypertensive efficacy of omapatrilat relative to enalapril, 47 and good efficacy was also shown in heart failure.…”

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

“…15,24 In earlier studies, the occurrence of angioedema was reported to be three times as frequent with omapatrilat as with enalapril (2.17 versus 0.68%). 15 Although AEs related to angioedema were not observed in the present study, this study was small (n ¼ 123) and of short duration (20 days in total).…”

“…Serial blood samples for ACE activity determination were collected in vacutainers at the following time points: pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 h post-dose on day 1; pre-dose, 0.5, 1, 2, 3,4,8,12,16,24,36 and 48 h post-dose on day 20. For atrial natriuretic peptide (ANP) concentration determination, blood samples were collected on days 1 and 20, at predose, 0.5, 1, 2, 4, 8, 12 and 24 h post-dose into chilled EDTA collection tubes containing a cocktail of protease inhibitors (aprotinin: 500 KIU/ml plasma, plus soybean trypsin inhibitor: 50 BAEE U/ml plasma).…”