The pharmacological profile of
YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)
biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri
azole potassium salt monohydrate, a novel non-
peptide angiotensin AT1 receptor antagonist, was studied in vitro and in vivo.
YM358 competed with [125I][Sar1, Ile8]
angiotensin II for
angiotensin AT1 receptors in rat liver membranes.
YM358 displayed competitive kinetics and the pKi value was calculated as 8.79. In contrast,
YM358 had little effect on the binding of [125I][Sar1, Ile8]
angiotensin II to the
angiotensin AT2 receptor in bovine cerebellum. In isolated rabbit aorta,
YM358 produced a parallel rightward shift in the concentration-response curve for
angiotensin II with a pA2 value of 8.82.
YM358 had no effect on the contraction induced by KCl,
norepinephrine,
serotonin,
histamine,
prostaglandin F2alpha or
endothelin-1 even
at 10(-5) M. On the basis of pKi values in the binding assay and pA2 values in the isolated tissues,
YM358 was approximately 3-10 times more potent than
losartan in antagonizing
angiotensin AT1 receptors. In pithed rats,
intravenous administration of
YM358 inhibited an increase in mean blood pressure induced by
intravenous infusion of
angiotensin II in a dose-dependent manner. In conscious normotensive rats,
YM358 at 3-30 mg/kg p.o. inhibited the
angiotensin II-induced pressor response in a dose-dependent manner.
YM358 at 30 mg/kg caused maximum and complete inhibition 30 min after dosing, and inhibition lasted more than 24 h. These results demonstrate that
YM358 is a potent, AT1-selective and competitive nonpeptide
angiotensin receptor antagonist. Moreover,
YM358 is both orally active and long-lasting. This pharmacological profile suggests that
YM358 would be suitable for the treatment of cardiovascular disorders such as
hypertension and chronic
heart failure.