Heterocyclic lactam derivatives as dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibitors

A series of 13- and 14-membered ring lactam derivatives 1-thia-4-azacyclotridecane derivatives (9a,b, 10, 11), and 1-thia-4-azacyclotetradecane derivative (12a-c) was prepared from L-cysteine. Compounds (9a,b) and (12a,b) were tested in vitro for inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition. The structure-activity profile of the series is discussed. Compound (9b), a 13-membered ring macrocyclic lactam, had an NEP IC 50 of 18 nM and an ACE IC 50 of 12 nM in vitro and showed dual plasma inhibition after intravenous or oral administration