Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist.
CS-866, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1- methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)-phenyl]phenyl)met hylimidazol- 5-carboxylate, a prodrug type angiotensin receptor antagonist, is deesterified to the active acid, RNH-6270. RNH-6270 inhibited [125I]angiotensin II binding to bovine adrenal cortical membranes (angiotensin AT1 receptors) with an IC50 value of 7.7 nM, but not [125I]angiotensin II binding to bovine cerebellar membranes (angiotensin AT2 receptors), indicating the selectivity of the compound for angiotensin AT1 receptors. In guinea pig aortas, RNH-6270 reduced the maximal response of the concentration-contractile curve for angiotensin II (pD'2 = 9.9), but had no effect on the contractile response induced by phenylephrine or KCl. In conscious rats, intravenously injected RNH-6270 inhibited angiotensin II-induced pressor responses in a dose-dependent manner, and orally administered CS-866 produced a long-lasting inhibition of angiotensin II pressor responses. SK&F-525A, a P-450 inhibitor, suppressed the angiotensin II inhibitory effect of losartan, but not that of CS-866. These results demonstrate that RNH-6270 is a potent and AT1-selective angiotensin receptor antagonist and that, after oral administration, CS-866 has a long-lasting angiotensin II inhibitory action which is not affected by drug metabolizing enzymes in the liver.
Mizuno
M
M
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Sada
T
T
Ikeda
M
M
Fukuda
N
N
Miyamoto
M
M
Yanagisawa
H
H
Koike
H
H
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000758:Anesthesia; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D006168:Guinea Pigs; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D000068557:Olmesartan Medoxomil; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013777:Tetrazoles / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil