NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF BENZIMIDAZOLES

A series of substituted 2-butylbenzimidazoles bearing a biphenylylmeth yl moiety at the 1-position was prepared via three synthetic routes an d evaluated for angiotensin II (AII) receptor antagonistic activity (i n vitro and in vivo). Binding affinity was determined using bovine adr enal cortical membrane. Substitution at the 4-, 5-, or 6-position redu ced the affinity relative to that of the unsubstituted compound (13a). However, most of the compounds with a substituent at the 7-position s howed binding affinity comparable to that of DuP 753 (losartan). In fu nctional studies, a carboxyl group was found to be very important for antagonistic activity against AII. Comparison of 2-butyl-1-[[2'-(1H-te trazol-5-yl)biphenyl-4-yl] methyl]-1H-benzimidazole-4-,-5-,-6-, and -7 -carboxylic acids (15a-d) in an AII-induced rabbit aortic ring contrac tion assay clearly demonstrated the importance of the substitutional p osition of the carboxyl group. In an in vivo assay, oral administratio n of benzimidazole-7-carboxylic acids caused long-lasting inhibition o f the AII-induced pressor response in rats. The optimum substituent at the 7-position of the benzimidazole ring was found to be a carboxyl o r an ester group. The representative compound, iphenyl-4-yl]methyl]-1H -benzimidazole-7-carboxylic acid (15d, CV-11194), inhibited the specif ic binding of [I-125]AII to bovine adrenal cortical membrane with an I C50 value of 5.5 x 10-7 M. The AII-induced contraction of rabbit aorti c strips was antagonized by CV-11194 (IC50 value, 5.5 x 10(-11) M), wh ile the compound had no effect on the contraction induced by norepinep hrine or KCl. Orally administered CV-11194 at doses of 0.3-10 mg/kg do se-dependently inhibited the AII-induced pressor response in rats and dogs. CV-11194 at 1 mg/kg po reduced blood pressure in spontaneously h ypertensive rats (SHR). The three-dimensional molecular structure of C V-11194 was determined by X-ray diffraction.