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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.
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