NEW ALPHA-THIOL DIPEPTIDE DUAL INHIBITORS OF ANGIOTENSIN-I CONVERTING-ENZYME AND NEUTRAL ENDOPEPTIDASE EC-3.4.24.11

Dual inhibitors of the two zinc metallopeptidases, neutral endopeptida se (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 we re evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excelle nt dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) presser response in conscious rats when given by intravenous administration. Compound 6n, one of our most pot ent dual inhibitors in vitro, was found to be more efficacious than ca ptopril in the AI presser experiment when administered orally to consc ious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficaci ous than acetorphan. The structure-activity relationships and biologic al activity of these dual inhibitors will be discussed.