title: Discovery of a well-absorbed, efficacious renin inhibitor, A-74273.
abstract: The development of orally active renin inhibitors has been plagued by limited bioavailability in animals and humans. A-74273 is a novel, potent nonpeptide inhibitor of human renin (IC50 = 3.1 nM). This compound was absorbed into the portal and systemic circulations of anesthetized rats, ferrets, monkeys, and dogs after intraduodenal dosing. This favorable pattern also was observed after oral dosing in conscious animals, except in monkeys. Hepatic extraction of A-74273 was more efficient in rats and monkeys than in dogs or ferrets. A-74273 modestly inhibits dog renin, and when given orally as the base (0, 0.3, 1, 3, 10, and 30 mg/kg; n = 8 per dose) to conscious, salt-depleted dogs it induced dose-related reductions in mean arterial pressure and plasma renin activity. Peak falls in mean arterial pressure from normotensive baselines were -14 +/- 1, -26 +/- 3, and -44 +/- 3 mm Hg for the 3, 10, and 30 mg/kg groups, respectively (p < 0.05). Baseline plasma renin activity values (10.9 +/- 1.1-12.7 +/- 1.1 ng angiotensin I/ml/hr) were maximally inhibited, ranging from 43 +/- 8% at 0.3 mg/kg to 98 +/- 1% at 30 mg/kg. Bioavailability in this model was estimated to be 54 +/- 13% when plasma drug levels were determined by a renin inhibitory activity assay, but bioavailability was lower when compared with high-performance liquid chromatographic analysis of A-74273. This discrepancy was accounted for by the identification of structurally similar metabolites that are as active as the parent drug against human renin but much less potent against dog renin.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Abbott Laboratories, Cardiovascular Research Division, Abbott Park, IL 60064.
authors.forename: H D
authors.initials: HD
authors.lastname: Kleinert
authors.forename: H H
authors.initials: HH
authors.lastname: Stein
authors.forename: S
authors.initials: S
authors.lastname: Boyd
authors.forename: A K
authors.initials: AK
authors.lastname: Fung
authors.forename: W R
authors.initials: WR
authors.lastname: Baker
authors.forename: K M
authors.initials: KM
authors.lastname: Verburg
authors.forename: J S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: P
authors.initials: P
authors.lastname: Kovar
authors.forename: J
authors.initials: J
authors.lastname: Barlow
authors.forename: J
authors.initials: J
authors.lastname: Cohen
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000577:Amides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004039:Diet, Sodium-Restricted; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011323:Primates; D051381:Rats; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D009025:Morpholines; D000092502:Renin Inhibitors; C078248:A 74273