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

Masayuki Shibasaki, Akira Fujimori, Masahiro Takanashi, Toshiyuki Kusayama, Tomoko Tokioka, Yasuko Satoh, Toshio Okazaki, Wataru Uchida, Osamu Inagaki, Isao Yanagisawa

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11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)167-173
Number of pages7
JournalEuropean Journal of Pharmacology
Issue number2-3
Publication statusPublished - 1997 Sept 24


  • Angiotensin AT receptor antagonist
  • Angiotensin II
  • Losartan
  • YM358


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