title: Pharmacology of LR-B/081, a new highly potent, selective and orally active, nonpeptide angiotensin II AT1 receptor antagonist.
abstract: 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) AT1-receptor, was studied in vitro and in vivo. 2. In rabbit aortic strips incubated with LR-B/081 (1-1,000 nM), 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 pKB = 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 AT1-antagonist. Contractions elicited by KCl or phenylephrine were not affected by 10 microM LR-B/081. 3. In rat isolated perfused kidney, LR-B/081 and losartan antagonized the AII-induced vasoconstriction [IC50 (95% confidence limits) = 17(13-24) and 39(32-54) nM, respectively]. The LR-B/081 antagonism was incompletely reversed by excess AII, while losartan was fully displaced. The IC50 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 mumol 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 All, indicating that in vivo the interaction of LR-B/081 with All receptors is reversible. LR-B/081 at 6 micromol 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 micromol kg-1 markedly inhibited the All-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 (ED40mmHg(95% confidence limits) = 0.50(0.36-0.70) and 0.86(0.57-1.3) micromol kg-1, respectively). A single intravenous(2 micromol kg-1) or oral (6 micromol 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 micromol 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 micromol kg-1LR-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 All at the AT1-receptor subtype, which markedly lowers the blood-pressure in conscious renal and spontaneously hypertensive rats.
authors.affiliation: Department of Pharmacology of Laboratori Guidotti, Pisa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Cirillo
authors.forename: A R
authors.initials: AR
authors.lastname: Renzetti
authors.forename: P
authors.initials: P
authors.lastname: Cucchi
authors.forename: M
authors.initials: M
authors.lastname: Guelfi
authors.forename: A
authors.initials: A
authors.lastname: Salimbeni
authors.forename: S
authors.initials: S
authors.lastname: Caliari
authors.forename: A
authors.initials: A
authors.lastname: Castellucci
authors.forename: S
authors.initials: S
authors.lastname: Evangelista
authors.forename: A
authors.initials: A
authors.lastname: Subissi
authors.forename: A
authors.initials: A
authors.lastname: Giachetti
mesh_terms: D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; C094835:LR B-081; D011744:Pyrimidinones; D013876:Thiophenes