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}methylimidazol-5-carboxylate, a prodrug type angiotensin receptor antagonist, is deesterified to the active acid, RNH-6270. RNH-6270 inhibited [I-125]angiotensin II binding to bovine adrenal cortical membranes (angiotensin AT(1) receptors) with an IC50 value of 7.7 nM, but not [I-125]angiotensin II binding to bovine cerebellar membranes (angiotensin AT(2) receptors), indicating the selectivity of the compound for angiotensin AT(1) 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 presser responses in a dose-dependent manner, and orally administered CS-866 produced a long-lasting inhibition of angiotensin II presser 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 AT(1)-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.