Abstract
The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II1. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states2–4. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril)5,6 and MK-421 (enalapril maleate)7–9 which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10−9−10−8 M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).
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References
Peach, M. J. Physiol. Rev. 57, 313–370 (1977).
MacGregor, G. A., Markandu, N. D., Roulston, J. E., Jones, J. C. & Morton, J. J. Nature 291, 329–331 (1981).
Laragh, J. H. Clin. ex. Hypertens. 2, 525–552 (1980).
Skeggs, L. T., Dorer, F. E., Kahn, J. R., Lentz, K. E. & Levine, M. in Topics in Hypertension (ed. Laragh, J. H. ) 1–20 (Yorke Medical, New York, 1980).
Ondetti, M. A., Rubin, B. & Cushman, D. W. Science 196, 441–444 (1977).
Atkinson, A. B. & Robertson, J. I. S. Lancet ii, 836–839 (1979).
Patchett, A. A. et al. Nature 288, 280–283 (1980).
Biollaz, J. et al. J. cardiovascular Pharmac. 4, 966–972 (1982).
Hodsman, G. P. et al. Br. med. J. 285, 1697–1699 (1982).
Burton, J., Poulsen, K. & Haber, E. Biochemistry 14, 3892–3898 (1975).
Poulsen, K., Haber, E. & Burton, J. Biochim. biophys. Acta 452, 533–537 (1976).
Szelke, M. et al. Hypertension 4, II-59–69 (1981).
Szelke, M. et al. Nature 299, 555–557 (1982).
Umezawa, H. et al. J. Antibiot. 23, 259–262 (1970).
Gross, F., Lazar, J. & Orth, H. Science 175, 656 (1971).
Marciniszyn, J., Hartsuck, J. A. & Tang, J. J. biol. Chem. 251, 7088–7094 (1976).
Workman, R. J. & Burkitt, D. W. Archs Biochem. Biophys. 194, 157–164 (1979).
Skeggs, L. T., Lentz, K. E., Kahn, J. R. & Hochstrasser, H. J. exp. Med. 128, 13–34 (1968).
Fruton, J. S. Adv. Enzym. 44, 1–36 (1976).
Powers, J. C., Harley, A. D. & Myers, D. V. in Acid Proteases-Structure, Function and Biology (ed. Tang, J. ) 141–157 (Plenum, New York, 1977).
Wolfenden, R. A. Rev. Biophys. Bioengng 271–306 (1976).
Rich, D. H., Sun, E. T. O. & Ulm, E. J. med. Chem. 23, 27–33 (1980).
Dixon, M. Biochem. J. 55, 170–171 (1953).
Barany, G. & Merrifield, R. B. in The Peptides Vol. 2 (eds Gross, E. & Meienhofer, J.) 1–284 (Academic, New York, 1979).
Rich, D. H., Sun, E. T. & Bopari, A. S. J. org. Chem. 43, 3624–3626 (1978).
Haber, E., Koerner, T., Page, L. B., Kliman, B. & Purnode, A. J. clin. Endocr. 29, 1349–1355 (1969).
Tikkanen, I., Fyhrquist, F. & Puutula-Räsänen, L. Clin. Sci. 59, 381–383 (1980).
Poe, M., Wu, J. K., Florance, J. R., Rodkey, J. A., Bennett, C. D. & Hoogsteen, K. J. biol. Chem. 258, 2209–2216 (1983).
Bangham, D. R., Robertson, I., Robertson, J. I. S., Robinson, C. J. & Tree, M. Clin. Sci. mol. Med. 48 (Suppl. 2), 135s–159s (1975).
Cha, S. Biochem. Pharmac. 24, 2177–2185 (1975).
Lin, T.-Y. & Williams, H. R. J. biol. Chem. 254, 11875–11883 (1979).
Medzihradszky, K., Voynick, I. M., Medzihradszky-Schweiger, H. & Fruton, J. S. Biochemistry 9, 1154–1162 (1967).
Knight, C. G. & Barrett, A. J. Biochem. J. 155, 117–125 (1976).
Morrison, J. F. Biochim. biophys. Acta 185, 269–286 (1969).
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Boger, J., Lohr, N., Ulm, E. et al. Novel renin inhibitors containing the amino acid statine. Nature 303, 81–84 (1983). https://doi.org/10.1038/303081a0
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DOI: https://doi.org/10.1038/303081a0
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