Nonpeptide Angiotensin II Receptor Antagonists. Synthesis and Biological Activity of Benzimidazolecarboxylic Acids

Article abstract of DOI:10.1021/jm00067a016

A series of 2-substituted-1-<(biphenyl-4-yl)methyl>-1H-benzimidazole-7-carboxylic acids was prepared from the key intermediate 3-amino-2-<<(biphenyl-4-yl)methyl>amino>benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-<<2'-(1H-tetrazol-5-yl)biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist.The AII antagonistic activity of the benzimidazoles 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 AII receptor (IC50 value, 10^-6-1-^-7 M) and inhibited the AII-induced pressor response 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 response 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, lipohilicity, and electronic effects affected the potency of the AII antagonistic action.Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect.The representative compound, 2-ethoxy-1-<<2'-(1H-tetrazol-5-yl)biphenyl-4-yl>methyl>-1H-benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of <125I>AII to bovine adrenal cortical membrane with an IC50 value of 1.1*10^-7 M.The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0*1-^-10 M).Oral administration of CV-11974 to conscious normatensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response.CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.