Discovery of a well-absorbed, efficacious renin inhibitor, A-74273.

Abstract

Hie 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 (1050=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, 03, 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±l.l-12.7±l.l ng angiotensin I/ml/hr) were maximally inhibited, ranging from 43±8% at 03 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. Despite overall lower in vitro activity in dog plasma than in human plasma, A-74273 is an active prodrug that is orally efficacious in dogs. 2 The effector hormone angiotensin II (Ang II) is primarily formed as a result of two sequential reactions catalyzed by renin and angiotensin converting enzyme (ACE), in that order. The inhibition of ACE is of notable therapeutic value in the treatment of hypertension and congestive heart failure. -4 More than likely, the hemodynamic activity of ACE inhibitors is mediated through inhibition of the RAS, 5 -6 but the observed side effects associated with this line of therapy (e.g., cough and angioedema) may be attributed to the promiscuous nature of ACE in recognizing a host of functionally active peptide substrates such as bradykinin, neuropeptide Y, and substance P. 7The inhibition of renin as the site of RAS blockade has several virtues. Renin inhibition interrupts the synthesis of Ang II at the first and rate-limiting step of the biochemical cascade, precluding the accumulation of bioactive products. Further, the high degree of

Hemodynamic Effects of Renin Inhibitors

“…The standard errors are quite small for A-74273, suggesting consistency, rather than the high variability shown for enalkiren. The calcu lated bioavailabilities after intraduodenal dosing were never higher than 2% for enalkiren in any species tested, but were 16% in the monkey, 24% in the rat, 28% in the ferret, and 27% in the dog for A-74273 [10]. A-74273 was not tested in man.…”

“…Several classes of chemical structures, including dipeptide-core organic mole cules and nonpeptides, have been shown to be well absorbed [9,10]. Based on published data regarding the physical prop erties.…”

“…7]. The most successful concept to date is represented by transition-state substrate analogs [8] of the angiotensinogen-renin complex, with dipeptide cores or the equivalent [6,9,10], The crystal structure of renin has been reported [II]. Fig.…”

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42–5892) in hypertensive patients

“…For remikiren this is the consequence of low absorption and -more important-of high liver first-pass effect [14]. Hence, efforts are being made to synthesize non-peptidic renin inhibitors with higher oral bioavailabity [28]. In spite of the low bioavailability remikiren should be an effacious drug in terms of plasma renin inhibition following oral administration, since plasma concentrations above the in vitro IC5o of 0.8 nM (0.5 ng ml-') were [11,13,14,29,30] and in hypertensive patients [12].…”

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys

“…Isolated perfused rat liver studies demonstrated very rapid hepatic uptake and metabolism of CI-992 [11], indicating that low bioavailability is in part due to hepatic first-pass metabolism. Larger interspecies differences in bioavailability were observed for other renin inhibitors [13,14]. Thus it is difficult to extrapolate from pharmacologically active doses in animals to clinically effective doses with certainty.…”