Highly potent and specific inhibitors of human renin.
Small peptide analogues representing the C-terminal portion of angiotensin I sequence were designed as inhibitors of human renin. Among synthesized compounds, benzyloxycarbonyl (-"Z")-(1-naphthyl)Ala-His-leucinal (ES-188), Z-(1-naphthyl)Ala-His-statine ethyl ester (ES-226), and Z-(1-naphthyl)Ala-His-statine 2-methylbutylamide (ES-254) markedly inhibited human and primate renins (inhibitory concentration, 50% [IC50], near 10(-7) M). These peptide analogues inhibited rabbit renin with one or two orders of magnitude less potency. They were very weak inhibitors of renins from pig, goat, dog, and rat. ES-188 had no discernible effect on cathepsin D, pepsin, or human angiotensin-converting enzyme at the concentration of 10(-4)M. ES-226 had little effect on the three enzymes at the concentration of 10(-5)M; however, ES-254 had a considerable inhibitory effect on cathepsin D (IC50 of 1.4 X 10(-5)M), pepsin (IC50 of 4.2 X 10(-5)M), and human angiotensin-converting enzyme (IC50 of 7.1 X 10(-6)M). Our results indicate that 1-naphthylalanine-containing tripeptide analogues are highly potent human renin inhibitors.
Kokubu
T
T
Hiwada
K
K
Murakami
E
E
Imamura
Y
Y
Matsueda
R
R
Yabe
Y
Y
Koike
H
H
Iijima
Y
Y
D000803:Angiotensin I / Q000096:biosynthesis; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D000937:Antigen-Antibody Reactions; D002403:Cathepsins / Q000378:metabolism; D004791:Enzyme Inhibitors; D006801:Humans; D010434:Pepsin A / Q000378:metabolism; D010436:Pepstatins / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000808:Angiotensinogen; D002403:Cathepsins; D004791:Enzyme Inhibitors; D010434:Pepsin A; D010436:Pepstatins; D007703:Peptidyl-Dipeptidase A; D000092502:Renin Inhibitors; C014195:Streptomyces pepsin inhibitor; C031375:pepstatin