Pharmacology of LR‐B/081, a new highly potent, selective and orally active, nonpeptide angiotensin II AT 1 receptor antagonist

1 The pharmacological profile of LR‐B/081, (methyl 2‐[[4‐butyl‐2‐methyl‐6‐oxo‐5‐[[2′‐(1H‐tetrazol‐5‐yl)[1,1′‐biphenyl]‐4‐yl]methyl]‐1(6H)‐pyrimidinyl]methyl]‐3‐thiophenecarboxylate), a novel antagonist at the angiotensin II (AII) AT 1 ‐receptor, was studied in vitro and in vivo. 2 In rabbit aortic strips incubated with LR‐B/081 (1–1,000 n m ), the concentration‐response curve to AII was displaced to the right in a nonparallel fashion and the maximal contraction was progressively reduced, indicating that the compound is an insurmountable antagonist in this preparation (apparent p K B = 9.50 ± 0.23). However, the interaction of LR‐B/081 with AII receptors was found to be reversible, since the maximal response to AII was restored by coincubation with losartan, a surmountable AII AT 1 ‐antagonist. Contractions elicited by KCl or phenylephrine were not affected by 10 μ m LR‐B/ 081. 3 In rat isolated perfused kidney, LR‐B/081 and losartan antagonized the AII‐induced vasoconstriction [IC 50 (95% confidence limits) = 17(13–24) and 39(32–54) n m , respectively]. The LR‐B/081 antagonism was incompletely reversed by excess AII, while losartan was fully displaced. The IC 50 values of LR‐B/081 and losartan obtained against vasoconstriction induced by endothelin‐1 and noradrenaline were two orders of magnitude higher. 4 In pithed rats, the intravenous administration of LR‐B/081 (0.2–2 μmol kg −1 ) dose‐dependently shifted to the right in a nonparallel fashion the dose‐pressor response curve to AII. The maximal pressor response to AII was reduced by LR‐B/081 in a dose‐dependent fashion. The coadministration of losartan induced a progressive recovery of the maximal pressor response to AII, indicating that in vivo the interaction of LR‐B/081 with AII receptors is reversible. LR‐B/081 at 6 μmol kg −1 , i.v. also did not affect the vasopressor response induced by noradrenaline in the pithed rat. 5 In conscious normotensive rats, single oral administration of LR‐B/081 at 6 μmol kg −1 markedly inhibited the AII‐induced pressor response; the inhibition lasted more than 24 h. 6 In conscious renal hypertensive rats, intravenous LR‐B/081 appeared as potent as losartan (ED 40mmHg (95% confidence limits) = 0.50(0.36–0.70) and 0.86(0.57–1.3) μmol kg −1 , respectively). A single intravenous (2 μmol kg −1 ) or oral (6 μmol kg −1 ) administration of LR‐B/081 induced a marked fall in blood pressure which lasted for at least 12 h. 7 In conscious spontaneously hypertensive rats, LR‐B/081 at 20 μmol kg −1 , p.o., induced a marked and sustained fall in blood pressure. The duration of the antihypertensive effect was longer than 12 h. Heart rate was not modified by LR‐B/081 treatment. Repeated oral administration of 17 μmol kg −1 LR‐B/081 for 16 days did not result in the development of tolerance. 8 These results demonstrate that LR‐B/081 is a potent, selective and orally active antagonist of AII at the AT 1 ‐receptor subtype, which markedly lowers the blood‐pressure in conscious renal and spontaneously hypertensive rats.