NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - SYNTHESIS AND BIOLOGICAL-ACTIVITY OF BENZIMIDAZOLECARBOXYLIC ACIDS

A series of iphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acids w as prepared from the key intermediate 3-amino-2-[[(biphenyl-4-yl)methy l]amino]benzoate (6a-c) in order to clarify the structure-activity rel ationships of various analogues of iphenyl-4-yl]methyl]-1H-benzimidazo le-7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity of the ben zimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats. Most of the benzimidazoles showed high affinity for the All receptor (IC50 value, 10(-6)-10(-7) M) and inhibited the AII-induced pressor re sponse at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753. The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor resp onse suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipophilicity, and electronic effects a ffected the potency of the AII antagonistic action. Both a carboxyl gr oup at the 7-position and a tetrazole ring at the 2'-position were par ticularly important for potent and orally active AII antagonistic acti vity and a long-acting hypotensive effect. The representative compound , l-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-ca rboxylic acid (26 b, CV-11974), inhibited the specific binding of [I-125]AII to bovine a drenal cortical membrane with an IC50 value of 1.1 X 10(-7) M. The AII -induced contraction of rabbit aortic strips was antagonized by CV-119 74 (IC50 value, 3.0 X 10(-10) M). Oral administration of CV-11974 to c onscious normotensive rats at 1 mg/kg resulted in long-lasting inhibit ion of the AII-induced pressor response. CV-11974 at 0.1-1 mg/kg iv re duced blood pressure dose-dependently in spontaneously hypertensive ra ts.