Pharmacological profile of YM358, a novel nonpeptide angiotensin AT₁ receptor antagonist

The pharmacological profile of YM358, 2,7-diethyl-5-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5 -b][1,2,4]triazole 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 pK(i) 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 F(2α) or endothelin-1 even at 10^-5 M. On the basis of pK(i) 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 presser 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.