Trans-(3S,4S)-Disubstituted Pyrrolidines as Inhibitors of the Human Aspartyl Protease Renin. Part I: Prime Site exploration using an amino linker

Recently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g. 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2