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

• Published in: European journal of pharmacology 1997-09, Vol.335 (2), p.167-173
• Main Authors: Shibasaki, Masayuki, Fujimori, Akira, Takanashi, Masahiro, Kusayama, Toshiyuki, Tokioka, Tomoko, Satoh, Yasuko, Okazaki, Toshio, Uchida, Wataru, Inagaki, Osamu, Yanagisawa, Isao
• Format: Article
• Language: English
• Subjects: Angiotensin AT 1 receptor antagonist; Angiotensin II; Angiotensin II - metabolism; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Antihypertensive agents; Antihypertensive Agents - pharmacology; Azoles - metabolism; Azoles - pharmacology; Binding, Competitive; Biological and medical sciences; Biphenyl Compounds - metabolism; Biphenyl Compounds - pharmacology; Blood Pressure - drug effects; Cardiovascular system; Cattle; Decerebrate State; Imidazoles - pharmacology; In Vitro Techniques; Losartan; Losartan - pharmacology; Male; Medical sciences; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiology; Pharmacology. Drug treatments; Pyridines - pharmacology; Rabbits; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles - pharmacology; YM358
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(97)01189-8

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.