Synthesis and Renin Inhibitory Properties of a New Soluble Pepstatin Derivative

Abstract

A new pepstatin derivative, pepstatinyl arginine methyl ester hydrochloride (pepstatinyl-Arg-O-Me), was synthesized with the aim of increasing water solubility without altering capacity to inhibit the renin—angiotensinogen reaction. Pepstatinyl-Arg-O-Me was shown to inhibit in vitro the reaction between either rat or purified hog renin and the natural rat renin substrate. In a fluorimetric assay, this derivative competitively inhibited the reaction between purified hog renin and a synthetic N-acetyl-tetradecapeptide renin substrate with a K_i of the same order of magnitude as that of pepstatin. In urethaneanesthetized ganglion-blocked rats, binephrectomized 24 hr before the experiments, both the plasma renin concentration and the rise in blood pressure following intravenous injection of hog renin were inhibited by pepstatinyl-Arg-O-Me disappeared within 60 min. Pepstatinyl-Arg-O-Me inhibited the 1.4 μmoles/kg. The in vivo inhibitory effect of 1.4 μmoles/kg of pepstatinyl-Arg-O-Me disappeared within 60 min. Pepstatinyl-Arg-Op-Me inhibited the reaction of endogenous and exogenous renin with plasma substrate both in vitro and in vivo.