title: Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy.
abstract: 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.
authors.affiliation: Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: H D
authors.initials: HD
authors.lastname: Kleinert
authors.forename: S H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: W R
authors.initials: WR
authors.lastname: Baker
authors.forename: H H
authors.initials: HH
authors.lastname: Stein
authors.forename: V
authors.initials: V
authors.lastname: Klinghofer
authors.forename: J
authors.initials: J
authors.lastname: Barlow
authors.forename: K
authors.initials: K
authors.lastname: Spina
authors.forename: J
authors.initials: J
authors.lastname: Polakowski
authors.forename: P
authors.initials: P
authors.lastname: Kovar
authors.forename: J
authors.initials: J
authors.lastname: Cohen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006439:Hemodynamics / Q000187:drug effects; D010455:Peptides; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000092502:Renin Inhibitors
chemical_list: D010455:Peptides; D010879:Piperazines; D011480:Protease Inhibitors; D013844:Thiazoles; D000092502:Renin Inhibitors; C076903:zankiren hydrochloride