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.
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