In the treatment of
cardiovascular disease, it could be of therapeutic interest to associate the hypotensive effects due to the inhibition of
angiotensin II formation with the
diuretic and natriuretic responses induced by the protection of the endogenous
atrial natriuretic peptide (
ANP). Investigation of this hypothesis requires an orally active compound able to simultaneously inhibit
angiotensin-converting enzyme (ACE) and
neutral endopeptidase (NEP), which is involved in renal
ANP metabolism. Such compounds have been rationally designed by taking into account the structural characteristics of the active site of both
peptidases. Among them,
RB 105, N-[(2S,3R)-2-mercaptomethyl-1-oxo-3-phenylbutyl]-(S)-
alanine, inhibited NEP and ACE with Ki values of 1.7 +/- 0.3 nM and 4.2 +/- 0.5 nM, respectively.
Intravenous infusion of
RB 105 in conscious spontaneously hypertensive rats prevented the pressor response to exogenous
angiotensin I and potentiated the natriuretic response to
ANP. Infusion of
RB 105, at 2.5, 5, 10, 25, and 50 mg/kg per hr decreased blood pressure dose-dependently in conscious catheterized spontaneously hypertensive rats and increased diuresis and natriuresis. Infusion of
RB 105 as a bolus of 25 mg/kg followed by 25 mg/kg per hr similarly decreased blood pressure and increased natriuresis in three different models of
hypertension (renovascular,
deoxycorticosterone acetate-
salt, and spontaneously hypertensive rats).
Mixanpril, a lipophilic
prodrug of
RB 105 (ED50 values when given orally to mice, 0.7 mg/kg for NEP; 7 mg/kg for ACE), elicited dose-dependent hypotensive effects of long duration in spontaneously hypertensive rats after
oral administration [-37 mmHg for 50 mg/kg twice a day (1 mmHg = 133 Pa) and is therefore the first dual NEP/
ACE inhibitor potentially useful for clinical investigations.