Journal of Medicinal Chemistry 1987-03-01

alpha-Methylproline-containing renin inhibitory peptides: in vivo evaluation in an anesthetized, ganglion-blocked, hog renin infused rat model.

S Thaisrivongs, D T Pals, J A Lawson, S R Turner, D W Harris

Index: J. Med. Chem. 30(3) , 536-41, (1987)

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Abstract

A structure-activity analysis of peptides containing backbone C alpha-methyl modification at the P4 site of the angiotensinogen sequence led to the discovery of potent renin inhibitors with apparent in vitro metabolic stability. Boc-alpha-MePro-Phe-His-Leu psi[CHOHCH2]Val-Ile-Amp dicitrate (Va) is a potent inhibitor of human plasma renin with an IC50 value of 1.8 nM. This peptide was shown not to be degraded in vitro by chymotrypsin, elastase, pepsin, and a rat liver homogenate preparation. It is also a potent inhibitor of hog renin with an IC50 value of 1.6 nM and was shown to elicit in vivo activity and cause dose-dependent hypotensive responses when given intravenously to anesthetized ganglion-blocked, hog renin infused rats.