New .alpha.-Thiol Dipeptide Dual Inhibitors of Angiotensin-I-Converting Enzyme and Neutral Endopeptidase EC 3.4.24.11

Abstract

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of alpha-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.

A Comprehensive Review of the Pharmacodynamics, Pharmacokinetics, and Clinical Effects of the Neutral Endopeptidase Inhibitor Racecadotril

“…A similar study reported an IC 50 of 1.8 nM for thiorphan with racecadotril being 1000 times less potent and acetyl-thiorphan having a value of 316 nM (Lambert et al, 1993, 1995). For in vitro inhibition of rat kidney NEP an IC 50 of 5.4 nM was reported (Fink et al, 1995), apparently reflecting in vitro conversion to thiorphan as shown before in rat brain (Lecomte et al, 1986). …”

CGS 30440: A Dual Inhibitor of Angiotensin‐Converting Enzyme and Neutral Endopeptidase 24.11

“…ACE was purified from rabbit lung and NEP from rat kidney membranes. These experiments indicated that CGS 30440 had IC 50 values of 19 nM for ACE and 2.2 nM for NEP (12,23). Under the conditions used in our in vitro assays, the selective ACE inhibitors captopril and enalaprilat exhibited IC 50 values of 10 and 9 nM, respectively, whereas the selective NEP inhibitor thiorphan had an IC 50 value of 5 nM (23).…”

“…In an attempt to improve their in vivo efficacy, a strategy was developed to prepare molecules where the amino acids were replaced with non-natural amino acids that would not impair the in vitro potency of these molecules but might improve their metabolic stability. This approach lead to a series of spirocyclic and gem-disubstituted dipeptides that were potent inhibitors of ACE and NEP activity in vitro and in vivo (23). The structure activity relationships of these compounds are outlined in Figure 2.…”

Pharmacological modulation of the natriuretic peptide system

“…Therefore, modifications were made at the thiol functional group. O-methyl, ethyl ester S-acetate modification at the thiol end led to the compound CGS-30440, which showed predominant NEP inhibitory activity, modest ACE inhibitory activity and improved metabolic stability ( Figure 5) [126]. The bioactivity of CGS-30440 is thought to be due to CGS-30008, an active metabolite (Figure 5).…”