NEW NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS .3. SYNTHESIS, BIOLOGICAL PROPERTIES, AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2-ALKYL-4-(BIPHENYLYLMETHOXY)PYRIDINE DERIVATIVES

A novel series of nonpeptide angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylyltetrazole moiety f ound in previously described antagonists via a methyleneoxy chain to t he 4-position of a 3-substituted 2,6-dialkylpyridine. When evaluated i n an in vitro binding assay using a guinea pig adrenal membrane prepar ation, compounds in this series generally gave IC50 values in the rang e 0.005-0.5 muM. A variety of substituents was found to be effective a t the 3-position of the pyridine ring. On intravenous administration i n a normotensive rat model, the more potent compounds inhibited the AI I-induced pressor response with ED50 values in the range 0.1-1.0 mg/kg . One of the compounds, -(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy}quino line (26), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg po in AII-infused, conscious, normotensive ra ts, the compound exhibited a dose-related inhibition of the pressor re sponse with a good duration of action at the higher doses. In a renal hypertensive rat model compound 26 showed a rapid and sustained loweri ng of blood pressure at a dose of 5 mg/kg po. Based on its profile, th is compound, designated ICI D6888, has been selected for evaluation in volunteers.