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Science 25 September 1992:
Vol. 257. no. 5078, pp. 1940 - 1943
DOI: 10.1126/science.1411510
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Articles

Science, Vol 257, Issue 5078, 1940-1943
Copyright © 1992 by American Association for the Advancement of Science

articles

Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy

HD Kleinert, SH Rosenberg, WR Baker, HH Stein, V Klinghofer, J Barlow, K Spina, J Polakowski, P Kovar, J Cohen, and al. et

Abbott Laboratories, Abbott Park, IL 60064.

Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. These findings support the potential of peptide-based drugs for oral administration.


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