NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS .3. STRUCTURE-FUNCTION STUDIES

  • 1 September 1989
    • journal article
    • research article
    • Vol. 250  (3) , 867-874
Abstract
A series of 1-benzylimidazole-5-acetate derivatives defining the critical substituents on the phenyl ring synthesized in order to improve on the affinity of 2-butyl-4-chloro-1-(2-nitrobenzyl)imidazole-5-acetate, sodium (S-8308) for the angiotensin II (AII) receptor. The analogs (see fig. 1 for structures), substituted with -1-(4-carboxybenzyl) (EXP6155), -1-[4-(carboxybenzamido)benzyl] (EXP6159) and the 5-methylacetate of EXP6159 (EXP6803), were found to inhibit the binding of [3H]AII to AII receptors in rat adrenal cortical microsomes with 9-, 35- and 107-fold higher affinity, respectively, than that of S-8308 (IC50, 15 .times. 10-6 .mu.M). Scatchard analysis of the [3H]AII binding revealed that in the presence of EXP6155 (10-6 M), the dissociation constant for ALL was increased from 1.2 to 3.9 .times. 10-9 M, whereas the total number of binding sites remained unchanged, suggesting a competitive nature of antagonism. A similar order of affinity or potency (saralasin .mchgt. EXP6803 > EXP6159 > EXP6155 > S-8308) was observed in various in vitro and in vivo assays: rat smooth muscle cells AII binding, 45Ca++ influx in rat aortic rings, contractile response in isolated rabbit aorta and AII-induced pressor response in anesthetized rats. Responses (45Ca++ and contraction) elicited by norepinephrine or by KCl were unaltered by these agents at concentrations of up to 10-4 M. In addition, they exerted no direct effect on the activity of rabbit angiotensin converting enzyme and rat renin. In conscious renal artery-ligated rats, EXP6155, EXP6159 and EXP6803 were p.o. inactive, but caused a rapid decrease in mean arterial pressure when administered i.v. The hypotensive effect of EXP6803 at a dose of 30 mg/kg lasted for more than 120 min. Our data demonstrate that the affinity of nonpeptide AII receptor antagonists can be improved while retaining the specificity and efficacy for inhibiting the renin-angiotensin system.