Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo

Abstract

A structure-activity analysis of peptides containing backbone C.alpha.-methyl and N.alpha.-methyl modifications led to the discovery of potent renin inhibitors with high metabolic stability. In vitro, Boc-Pro-Phe-N.alpha.-MeHis-Leu.psi.-[CHOHCH2]Val-Ile-Amp (XII) is a potent inhibitor of human plasma renin with IC50 of 0.26 nM. It is a much weaker inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (IC50 = 6 .mu.M). It was shown not to be degraded by a rat liver homogenate preparation. In vivo, it inhibited plasma renin activity and lowered blood pressure of furosemide-treated cynomolgus monkeys. At a dose of 5 mg/kg iv, the pronounced hypotensive response persisted for greater than 3 h postinfusion.