Discovery of inhibitors of human renin with high oral bioavailability

Abstract

Knowledge of the sequence of a bioactive protein (angiotensinogen) and the availability of a natural product inhibitor lead (pepstatin) were the starting point for discovery of potent penta- and hexapeptide renin inhibitors. Study of the metabolism and disposition of these substances forced the discovery of simpler inhibitors leading to the discovery of oral activity in Terlakiren. Modification of physical properties led to the synthesis of aminopiperidine, which was identified by oral efficacy profiling. Structural modification to give enzymatic stability produced the bioavailable benzylsuccinate inhibitor. Its bioactive monomethylamine metabolite (CP-108,671) was subsequently found to have uniformly high oral bioavailability and activity in various species including primates. This report illustrates a successful peptide-based approach to orally active and bioavailable series of pharmacologic agents.