PHARMACOLOGICAL PROFILE OF YM358, A NOVEL NONPEPTIDE ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST

The pharmacological profile of YM358, nyl-4-yl]methyl]-5H-pyrazolo[1,5 -b][1,2,4]triazole potassium salt monohydrate, a novel non-peptide ang iotensin AT(1) receptor antagonist, was studied in vitro and in vivo. YM358 competed with [I-125[Sar(1), Ile(8)]angiotensin II for angiotens in AT(1) receptors in rat liver membranes. YM358 displayed competitive kinetics and the pK(i) value was calculated as 8.79. In contrast, YM3 58 had little effect on the binding of [I-125][Sar(1), Ile(8)]angioten sin II to the angiotensin AT(2) receptor in bovine cerebellum. In isol ated rabbit aorta, YM358 produced a parallel rightward shift in the co ncentration-response curve for angiotensin II with a pA(2) value of 8. 82. YM358 had no effect on the contraction induced by KCI, norepinephr ine, serotonin, histamine, prostaglandin F-2 degrees or endothelin-1 e ven at 10(-5) M. On the basis of pK(i) values in the binding assay and pA(2) values in the isolated tissues, YM358 was approximately 3-10 ti mes more potent than losartan in antagonizing angiotensin AT(1) recept ors. In pithed rats, intravenous administration of YM358 inhibited an increase in mean blood pressure induced by intravenous infusion of ang iotensin II in a dose-dependent manner. In conscious normotensive rats . YM358 at 3-30 mg/kg p.o. inhibited the angiotensin II-induced presso r response in a dose-dependent manner. YM358 at 30 mg/kg caused maximu m and complete inhibition 30 min after dosing, and inhibition lasted m ore 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 pharmaco logical profile suggests that YM358 would be suitable for the treatmen t of cardiovascular disorders such as hypertension and chronic heart f ailure. (C) 1997 Elsevier Science B.V.