Abstract
Common problems in developing renin inhibitors are low solubility, insufficient oral absorption, and fast hepatic clearance. We focused on the molecular structure of renin inhibitors to overcome these problems. Cyclodextrins (CD) improved the low solubility of renin inhibitors, with β-CD showing the best ability to dissolve renin inhibitors. The intestinal absorption of renin inhibitors varied with both their solubility and molecular structure. Coadministration of β-CD improved the intestinal absorption of some renin inhibitors with low solubility as measured by transport into the mesenteric vein in the absorption experiment using the rat intestinal loop. Substitutions at both the N and C terminals was essential for absorption from the small intestine. A naphthyl group at the N-terminal further improved intestinal absorption. A carrier system appeared to be involved in the intestinal absorption of some renin inhibitors. N-methylation at the amide bond of thiazolylalanine suppressed the high hepatic clearance of one of the test compounds 18 which was well absorbed from the small intestine and it improved its oral bioavailability.
Similar content being viewed by others
REFERENCES
K. Poulsen, J. Burton, and E. Haber. Competitive inhibitors of renin. Biochemistry, 12:3877–3882 (1973).
E. Haber. Peptide inhibitors of renin in cardiovascular studies. Fed. Proc., 42:3155–3161 (1983).
J. Boger. Renin inhibition. In D. M. Bailey (ed.), Annual Reports in Medicinal Chemistry, Vol. 20, Academic Press, New York, 1985, pp. 257–266.
J. Boger. Clinical goal in sight for small molecule renin inhibitors. Trends Pharmacol. Sci. 8:370–372 (1987).
W. J. Greenlee. Renin inhibitors. Pharm. Res. 4:364–374 (1987).
P. Corvol, D. Chauveau, X. Jeunemaitre, and J. Menard. Human renin inhibitor peptides. Hypertension 16:1–11 (1990).
T. L. Blundell, J. Cooper, S. I. Foundling, D. M. Jones, B. Atrash, and M. Szelke. On the rational design of renin inhibitors. Biochemistry 26:5585–5590 (1987).
D. H. Rich. Pepstatin-derived inhibitors of aspartic proteinases (a close look at an apparent transition-state analogue inhibitor). J. Med. Chem. 28:263–273 (1985).
T. Kokubu, K. Hiwada, Y. Sato, T. Iwata, Y. Imamura, Y. Matsueda, R. Yabe, Y. Kogen, H. Yamazaki, Y. Iijima, and Y. Baba. Highly potent and specific inhibitors of human renin. Biochem. Biophys. Res. Commun. 118:929–933 (1984).
J. G. Dann, D. K. Stammers, C. J. Harris, R. J. Arrowsmith, D. E. Davies, G. W. Hardy, and J. A. Morton. Human renin. Biochem. Biophys. Res. Commun. 134:71–77 (1986).
S. R. Davio, M. M. McShane, T. J. Kakuk, R. M. Zaya, and S. L. Cole. Precipitation of the renin inhibitor ditekiren upon iv infusion; in vitro studies and their relationship to in vivo precipitation in the cynomolgus monkey. Pharm. Res. 8:80–83 (1991).
J. C. Greenfield, K. J. Cook, and I. A. O'Leary. Disposition, metabolism, and excretion of U-71038, a novel renin inhibitor peptide, in the rat. Drug Metabl. Disp. 17:518–525 (1989).
B. D. Rush, K. F. Wilkinson, W. Z. Zhong, S. K. Closson, D. B. Lakings, and M. J. Ruwart. Absolute oral bioavailability of ditekiren, a renin inhibitor peptide, in conscious rats. Inter. J. Pharm. 73:231–237 (1991).
T. T. Kararli, T. E. Needham, M. Griffin, G. Schoenhard, L. J. Ferro, and L. Alcorn. Oral delivery of a renin inhibitor compound using emulsion formulations. Pharm. Res. 9:888–893 (1992).
T. Kokubu, K. Hiwada, E. Murakami, S. Muneta, Y. Kitami, K. Oizumi, H. Takahagi, and H. Koike. An orally active inhibitor of human renin, ES-8891. Cardiovascular Drug Reviews 9:49–58 (1991).
H. W. Kleemann, H. Heitsch, R. Henning, W. Kramer, W. Kocher, U. Lerch, W. Linz, W. U. Nickel, D. Ruppert, H. Urbach, R. Utz, A. Wagner, R. Weck, and F. Wiegand. Renin inhibitory pentols showing improved enteral bioavailability. J. Med. Chem. 35:559–567 (1992).
S. H. Rosenberg, K. P. Spina, K. W. Woods, J. Polakowski, D. L. Martin, Z. Yao, H. H. Stein, J. Cohen, J. L. Barlow, D. A. Egan, K. A. Tricarico, W. R. Baker, and H. D. Kleinert. Studies directed toward the design of orally active renin inhibitors. 1. J. Med. Chem. 36:449–459 (1993).
S. H. Rosenberg, K. P. Spina, S. L. Condon, J. Polakowski, Z. Yao, P. Kovar, H. H. Stein, J. Cohen, J. L. Barlow, V. Klinghofer, D. A. Egan, K. A. Tricarico, T. J. Perun, W. R. Baker, and H. D. Kleinert. Studies directed toward the design of orally active renin inhibitors. 2. J. Med. Chem. 36:460–467 (1993).
S. Thaisrivongs, D. T. Pals, J. A. Lawson, S. R. Turner, D. W. Harris. α-Methylproline-containing renin inhibitory peptides. J. Med. Chem. 30:536–541 (1987).
S. Thaisrivongs, D. T. Pals, S. R. Turner, and L. T. Kroll. Renin inhibitory peptides. J. Hypertension. 7, Suppl., 2, S21–S23 (1989).
N. Muranushi, T. Yoshikawa, M. Nishiuchi, T. Oguma, K. Hirano, and H. Yamada. Characteristics of the intestinal absorption of 7432-S, a new orally active cephalosporin. 18th Symposium on Drug Metabolism and Action. abstr. 55–58 (1986).
W. Kramer, F. Girbig, U. Gutjahr, H. W. Kleemann, I. Leipe, H. Urbach, and A. Wagner. Interaction of renin inhibitors with the intestinal uptake system for oligopeptides and β-lactam antibiotics. Biochim. Biophys. Acta 1027:25–30 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hashimoto, N., Fujioka, T., Hayashi, K. et al. Renin Inhibitor: Relationship Between Molecular Structure and Oral Absorption. Pharm Res 11, 1443–1447 (1994). https://doi.org/10.1023/A:1018948007419
Issue Date:
DOI: https://doi.org/10.1023/A:1018948007419