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

doi:10.1021/JM00160A049

Paper

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

Published 1986 · S Thaisrivongs, D T Pals, D W Harris

Journal of medicinal chemistry

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45

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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.

Study Snapshot

Boc-Pro-Phe-N alpha-MeHis-Leu psi-[CHOHCH2]Val-Ile-Amp (XII) is a potent and specific renin inhibitor with high metabolic stability, lowering blood pressure in cynomolgus

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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

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