Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by tricyclic benzazepinone thiols

Various thioacyl analogs of CGS 28106, a tricyclic dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase, have been synthesized and their inhibitory potencies evaluated in vitro. The structure-activity relationship supports the proposed hypothesis that, despite its conformational constraints, CGS 28106 can inhibit the two distinct metalloproteases by adopting different binding modes. In addition, the structural features of CGS 28106 confer remarkable oral activity to this dual inhibitor, as measured by its ability to block the angiotensin-I pressor response and to potentiate plasma levels of atrial natriuretic peptide.