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

Abstract 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 AT 1 receptor antagonist, was studied in vitro and in vivo. YM358 competed with [ 125 I ][Sar 1 , Ile 8 ]angiotensin II for angiotensin AT 1 receptors in rat liver membranes. YM358 displayed competitive kinetics and the p K i value was calculated as 8.79. In contrast, YM358 had little effect on the binding of [ 125 I ][Sar 1 , Ile 8 ]angiotensin II to the angiotensin AT 2 receptor in bovine cerebellum. In isolated rabbit aorta, YM358 produced a parallel rightward shift in the concentration–response curve for angiotensin II with a pA 2 value of 8.82. YM358 had no effect on the contraction induced by KCl, norepinephrine, serotonin, histamine, prostaglandin F 2 α or endothelin-1 even at 10 −5 M. On the basis of p K i values in the binding assay and pA 2 values in the isolated tissues, YM358 was approximately 3–10 times more potent than losartan in antagonizing angiotensin AT 1 receptors. In pitched 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, AT 1 -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.