NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS, BIOLOGICAL-ACTIVITIES, AND STRUCTURE - ACTIVITY RELATIONSHIPS OF IMIDAZOLE-5-CARBOXYLIC ACIDS BEARING ALKYL, ALKENYL, AND HYDROXYALKYL SUBSTITUENTS AT THE 4-POSITION AND THEIR RELATED-COMPOUNDS

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and h ydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imid azole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced presser response by intravenous adm inistration. Various esters of these acids showed potent and long-last ing antagonistic activity by oral administration. The most promising c ompounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl (CS-866) and (pi valoyloxy)-methyl esters of l)-2-propyl-1-[(2'-1H-tetrazol-5-ylbipheny l-4-yl)- methyl]imidazole-5-carboxylic acid (26c). A study involving s tereochemical comp arisen of 26c with the acetylated C-terminal pentap eptide of AII was also undertaken.