Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by the orally active inhibitor mixanpril: a potential therapeutic approach in hypertension.

Abstract

In the treatment of cardiovascular disease, it could be of therapeutic Interest to associate the hypotensive effects due to the inhibition of lagotensn formation with the diuretic and natriuretic responses induced by the protection of the endogenous atrial natriuretic peptide (ANP) (14)(15)(16)(17) with no potassium loss (14, 16). However, these renal effects are not accompanied by significant changes in blood pressure or left ventricular hemodynamic load (14).Taken together, these results suggested the therapeutic interest ofa simultaneous inhibition ofACE, to avoid angiotensin II formation, and of NEP, to potentiate ANP action. Accordingly, the association ofselective inhibitors ofboth enzymes has been tested in various models of hypertension in rats, and a potentiation of their respective effects has been observed (18,19). Nevertheless, for reasons of bioavailability, pharmacokinetic parameters, and toxicity, it was more interesting to develop mixed inhibitors of NEP and ACE. The first dual inhibitor ofNEP and ACE, N(2-mercaptomethyl-3-phenylpropanoyl)-L-leucine was described >10 years ago (20)(21)(22). This compound, also designated SQ 28133, has been found to elicit depressor activity in both deoxycorticosterone acetate (DOCA)-salt hypertensive rats and spontaneously hypertensive rats (SHRs) after i.v. administration at high doses (100-300 mg/kg) (18). Another mixed inhibitor of NEP and ACE, alatriopril, has been also studied after i.v. administration in anesthetized rodents (23). This compound induces responses corresponding to ANP protection (diuresis, natriuresis, cGMP excretion) but does not significantly modify arterial pressure.In this paper, we describe a dual inhibitor ofNEP and ACE that is able to reduce blood pressure and to increase sodium excretion in different models ofhypertension. This molecule, RB 105, N-[(2S,3R)-2-mercaptomethyl-1-oxo-3-phenylbutyl]-(S)-alanine ( Fig. 1), designed by a rational approach including molecular modeling, inhibits NEP and ACE with K, values in the nanomolar range. After iLv. administration, RB 105 elicits the vascular and renal effects resulting from inhibition of both ANP metabolism and angiotensin II formation in conscious rats. Furthermore, mixanpril (Fig. 1), a prodrug of RB 105 which has an improved bioavailability allowing simultaneous inhibition of endothelial ACE (lung) and epithelial NEP (kidney), decreases blood pressure in SHRs after oral administration.Abbreviations: ACE, angiotensin-converting enzyme; NEP, neutral endopeptidase; ANP, atrial natriuretic peptide; SHR, spontaneously hypertensive rat; HACBO-Gly, N-[4(hydroxyamino)-1,4-dioxo-2-(phenylmethyl)butyl]glycine; DOCA, deoxycorticosterone acetate.o whom reprint requests should be addressed. 4072The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Vasopeptidase Inhibition Exhibits Endothelial Protection in Salt-Induced Hypertension

“…12,26,28 It is based on the simultaneous inhibition of two key enzymes, ACE and NEP, which are involved in the regulation of cardiovascular function in many ways. 19 This includes the metabolism of several vasoactive peptides such as angiotensin, natriuretic peptides, bradykinin, and ET-1 and their clearance from the circulation.…”

“…13,14,24,25 Inhibitors of both ACE and NEP, the socalled vasopeptidase inhibitors, lower blood pressure in a broader range of conditions than inhibition of ACE or NEP alone, independent of the activity of the renin-angiotensin system or the degree of salt retention. 26,27 Omapatrilat is a new vasopeptidase inhibitor that induces long-lasting antihypertensive effects in certain forms of experimental hypertension 20,23,28 greater than those elicited by selective inhibition of either enzyme alone. 21 Furthermore, omapatrilat lowers blood pressure and attenuates cardiac hypertrophy in diabetic hypertensive rats.…”

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

“…Known as vasopeptidase inhibitors (VPIs), these agents provide a potential therapeutic option to confer superior renoprotection in a state such as diabetes, particularly in the context of associated systemic hypertension. VPIs simultaneously inhibit ACE and NEP, thereby acting to decrease circulating levels of vasoconstrictor effector molecules such as angiotensin II (AII) as well as increasing the levels of vasodilatory agents such as atrial natriuretic peptide and bradykinin (BK) [12,13]. Previous research using the first of the VPIs, omapatrilat, has examined the beneficial effects on ameliorating developing clinical and experimental hypertension [14,15,16].…”

Identification of an Endothelin-converting Enzyme-2-specific Fluorigenic Substrate and Development of an in Vitro and ex Vivo Enzymatic Assay

“…There has also been considerable interest in the development of "dual" or "triple" inhibitors of NEP, ACE, and ECE-1 for applications in the cardiovascular field (36,37). Indeed, whereas ECE-1 and ACE are involved in the inactivation of the endothelin-1 and angiotensin II vasoconstrictive peptides, respectively, NEP regulates the half-life of the vasorelaxant natriuretic peptides.…”