Document Report Card

ID: ALA1123253

Journal: J Med Chem

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

Authors: Thaisrivongs S, Pals DT, Harris DW, Kati WM, Turner SR.

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 microM). 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.

CiteXplore: 3531518

DOI: 10.1021/jm00160a049