Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme with long duration of action.

Mercaptoacyl dipeptides, containing a glycine linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournié-Zaluski, M. C.; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S1, S1', and S2' subsites of this enzyme, (ii) and to interact with the S1' and S2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P.; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decrease in ACE inhibition. This shows that, in agreement with molecular modeling studies, a steric constraint as weak as a methyl group hinders optimal ACE active site recognition. Among these compounds, the dual inhibitor 26 (RB 106) (Ki, ACE = 0.35 nM; NEP = 1.6 nM) showed excellent pharmacokinetic properties with an almost complete in vivo inhibition of NEP and ACE for more than 4 h after oral administration in mice of a low dose (2.6 x 10(-5) mol/kg) of the inhibitor. Moreover, RB 106 remained active 12 h after oral administration. In spontaneous hypertensive rats, a chronic treatment of orally administered RB 106 (25 mg/kg/day) induced a prolonged hypotensive effect (-28 mmHg) still significant 2 days after the end of the treatment. In DOCA salt rats, a hypotensive response and a significant natriuresis were observed after i.v. administration. RB 106, which is one of the most potent dual inhibitors described to date, could have interesting clinical applications in long term treatment of congestive heart failure and myocardial ischemia.